Biology of Mitochondria in Neurodegenerative Diseases

Lee J Martin

doi:10.1016/B978-0-12-385883-2.00005-9

. Author manuscript; available in PMC: 2012 Dec 26.

Published in final edited form as: Prog Mol Biol Transl Sci. 2012;107:355–415. doi: 10.1016/B978-0-12-385883-2.00005-9

Biology of Mitochondria in Neurodegenerative Diseases

Lee J Martin ¹

PMCID: PMC3530202 NIHMSID: NIHMS428220 PMID: 22482456

Abstract

Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal degeneration in these familial diseases, and in the more common idiopathic (sporadic) diseases, are unresolved. Genetic, biochemical, and morphological analyses of human AD, PD, and ALS, as well as their cell and animal models, reveal that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and the overlying genetic variations. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial programmed cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This chapter reviews several aspects of mitochondrial biology and how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in AD, PD, and ALS.

I. Introduction

An understanding of mitochondrial biology that is relevant to adult-onset neurodegenerative disorders has emerged from multiple disciplines. Mitochondria are dynamic multifunctional organelles.¹ In addition to their critical role in the production of ATP through the electron transport chain (Fig. 1), these organelles function in intracellular Ca²⁺ homeostasis, synthesis of steroid, heme and iron–sulfur clusters, heat production, and programmed cell death (PCD).^1,3,4 Mitochondria are sites of formation of reactive oxygen species (ROS), including superoxide anion (O₂^•–)⁵ and the highly reactive hydroxyl radical (^•OH) or its intermediates,² and reactive nitrogen species such as nitric oxide (^•NO).⁶ Mitochondrial stress and morphology have important relationships to various cell death mechanisms that can be apoptotic, necrotic, or apoptosis–necrosis hybrids that emerge along a cell death continuum.⁷ Mitochondria have a variety of properties and functions (Fig. 1), discussed here, that might confer an intrinsic susceptibility of subsets of long-lived postmitotic cells, such as neurons, to aging and to stresses such as mutations and environmental toxins. Thus, it is reasonable that mitochondria could be involved in neurological disease. In fact, mitochondrial contribution to disease is found in disorders of acute interruptions in O₂ and substrate delivery to the brain; bioenergetic failure as seen in cerebral ischemia–reperfusion injury, trauma, and toxic exposures¹; and neurodegenerative diseases.⁷

Fig 1 — Mitochondrial regulation of neuronal cell life and death in schematic representation (adapted from an earlier form Ref. 7). Mitochondria (upper right) are multifunctional organelles (see text). Oxygen- and proton pump-driven ATP production by the electron transport chain (lower left) is one function. The respiratory chain proteins (complex I–IV) establish an electrochemical gradient across the IMM by extruding protons out of the matrix into the intermembrane space, thereby creating an energy gradient that drives the production of ATP by complex V (lower left). Superoxide (O₂^•–) is produced as a by-product in the process of electron transport and is converted to hydrogen peroxide (H₂O₂) by MnSOD (or Cu/ZnSOD in the intermembrane space). In pathological settings that can trigger cell aging and death, H₂O₂ can be converted to hydroxyl radical (^•OH), or hydroxyl-like intermediates, and mitochondrial nitric oxide synthase (NOS) can produce nitric oxide (NO) that can combine with O₂^•– to form peroxynitrite (ONOO^–). Cu/ZnSOD can use ONOO^– to catalyze the nitration (NO₂-Tyr) of mitochondrial protein tyrosine residues (bottom center) such as cyclophilin D (CyPD) and the adenine nucleotide translocator (ANT), which are core components of the mitochondrial permeability transition pore (PTP, another critical function of mitochondria). A third function of mitochondria is to regulate cell death. Bcl-2 family members regulate apoptosis by modulating the release of cytochrome c from mitochondria into the cytosol. Two models can account for this process, the Bax/Bak1 channel model and the mitochondrial apoptosis-induced channel (MAC). In the Bax/Bak1 channel model (left), Bax (Bcl-2-associated X protein) is a pro-apoptotic protein (Table I) found mostly in the cytosol in healthy mammalian cells but, after specific cell death-inducing stimuli, Bax undergoes a conformational change and translocates to the OMM, where it inserts. Bak1 (Bcl-2-antagonist/killer 1) is a similar pro-apoptotic protein localized mostly to the mitochondrial outer membrane. Bax/Bak1 monomers physically interact to form oligomeric or heteromeric channels that are permeable to cytochrome c. The formation of these channels is blocked by Bcl-2 and Bcl-x_L at multiple sites. BH3-only members (Bad, Bid, Noxa, Puma) are pro-apoptotic and can modulate the conformation of Bax/Bak1 to sensitize this channel, possibly by exposing its membrane insertion domain (not shown). The MAC could be a channel similar to the Bax/Bak1 channel, but it might also have additional components such as the voltage-dependent anion channel (VDAC). Released cytochrome c participates in the formation of the apoptosome, along with apoptotic protease activating factor 1 (Apaf1) and procaspase-9, in the cytosol that drives the activation of caspase-3. Second mitochondria-derived activator of caspases (Smac)/direct IAP-binding protein with low pI (DIABLO) are released into the cytosol to inactivate the anti-apoptotic actions of inhibitor of apoptosis proteins that inhibit caspases. The DNases apoptosis-inducing factor (AIF) and endonuclease G (EndoG) are released and translocate to the nucleus to stimulate DNA fragmentation. Another model (right) for mitochondrial-directed cell death involves the PTP. The PTP is a transmembrane channel formed by the interaction of ANT and VDAC at contact sites between the IMM and the OMM. CyPD, located in the matrix, can regulate the opening of the PTP by interacting with ANT. Opening of the PTP induces matrix swelling and OMM rupture, leading to release of cytochrome c and other apoptogenic proteins (AIF, EndoG). Certain Bcl-2 family members can modulate the activity of the PTP.

Several chronic neurodegenerative diseases are related causally to mitochondrial abnormalities. Optic atrophy type 1 (OPA1) is a hereditary optic neuropathy caused by mutations in the OPA1 gene that encodes a mitochondrial dynamin-related GTPase that functions in maintenance of mitochondrial morphology, including fusion, and metabolism.⁸ Charcot–Marie–Tooth disease, another autosomal-dominant neuropathy, is caused by mutations in the mitofusin 2 (MFN2) gene.⁹ Leber's hereditary optic neuropathy, a neurodegenerative disease that causes optic nerve atrophy and blindness in young adults, is linked to at least 11 different missense mutations in mitochondrial DNA (mtDNA) genes that encode subunits in enzyme complexes I, III, and IV that function in oxidative phosphorylation.¹⁰ Mutations in the polymerase γ (POLG1) gene, encoding the mtDNA polymerase catalytic subunit, are the most common causes of inherited mitochondrial disease in children and adults. These mutations are responsible for at least five phenotypes of neurodegenerative disease, including childhood myocerebrohepatopathy spectrum disorders, Alpers’ syndrome, ataxia neuropathy spectrum disorders, myoclonus epilepsy myopathy sensory ataxia, and chronic progressive external ophthalamoplegia (PEO).¹¹ Mutations in the ataxin-8 gene, encoding a protein called “twinkle” that functions as the replicative helicase for mtDNA, can cause infantile onset spinocerebellar ataxia and PEO.¹² Mitochondrial abnormalities caused by mutations in the adenine nucleotide translocator-1 (ANT1) gene can also cause PEO.¹³ Evidence for the involvement of mitochondria in other more common human adult-onset neurodegenerative disease is mostly circumstantial.⁷

This chapter summarizes several aspects of mitochondrial biology and the evidence for mitochondrial involvement in AD, PD, and ALS and some of their animal and cell models. In this regard, varying degrees of mitochondrial dysfunction and intrinsic mitochondrial-mediated cell death mechanisms could be critical determinants in the regulation of diseases and neurodegeneration, ranging along an apoptosis–necrosis cell death continuum.^7,14–16 Targeting mitochondrial properties, processes, or molecules, such as the mitochondrial permeability transition pore (mPTP)^17–20 (Fig. 2), could be important for developing new mechanism-based pharmacotherapies for these neurodegenerative diseases.

Fig 2 — The cell death continuum concept (modified from its original form Ref. 14). The concept as proposed in its original form envisions cell death as a spectrum. Apoptosis with internucleosomal fragmentation of genomic DNA (left) and necrosis with random digestion of genomic DNA (right) are at the extremes, and different syncretic hybrid forms are in between. The DNA gel at left shows a DNA fragmentation pattern typical of robust classical apoptosis (lane 2) and low amounts of apoptosis (lane 1) in developing rat brain (M is molecular weight markers in base pairs). The DNA gel at right shows a DNA fragmentation pattern typical of robust classical necrosis induced by brain hypoxia–ischemia (HI) and recovery of 3, 6, and 12h. Only intact genomic DNA is seen in sham control brain. The syncretic forms of cell death depicted are predicted to manifest depending on the severities or amplitudes of the changes in mitochondrial membrane potential (Δψ_m) oxidative stress, intracellular Ca²⁺ accumulation, and mitochondrial permeability transition pore (mPT) activation.

II. Some Aspects of Mitochondrial Biology Relevant to Neurodegeneration

A. Mitochondria and ROS

Mitochondria generate endogenous ROS as by-products of oxidative phosphorylation (Fig. 1).⁴ Because many mitochondrial proteins possess iron–sulfur clusters for oxidation–reduction reactions, and because mtDNA lacks protective histones, these macromolecules are particularly vulnerable to ROS attack.⁴ Electrons in the electron carriers, such as the unpaired electron of ubisemiquinone bound to coenzyme Q binding sites of complexes I–III, can be donated directly to O₂ to generate O₂^•–.⁴. O₂^• does not easily pass through biological membranes and is inactivated in compartments where it is generated.⁵ The mitochondrial matrix enzyme manganese superoxide dismutase (MnSOD or SOD2) or copper/zinc SOD (Cu/ZnSOD or SOD1) in the mitochondrial intermembrane space and cytosol convert O₂^•– to hydrogen peroxide (H₂O₂) in the reaction O₂^•–+O₂^•–+2H⁺ → H₂O₂+O₂ (Fig. 1).⁵ H₂O₂ is more stable than O₂^•– and can diffuse from mitochondria into the cytosol and nucleus. H₂O₂ is detoxified by glutathione peroxidase in mitochondria and the cytosol and by catalase in peroxisomes. In the presence of reduced transition metal (Fe²⁺), H₂O₂ is converted to ^•OH.² O₂^•– also can react with ^•NO, which can be synthesized by three isoforms of nitric oxide synthase (NOS) enzymes,⁶ to form the potent nucleophile oxidant and nitrating agent peroxynitrite (ONOO^–) (Fig. 1).²² ONOO^– or products of ONOO^– can damage proteins by nitration.²² ONOO^– is also directly genotoxic to neurons by causing single- and double-strand breaks in DNA.²³ Mitochondria produce NO.^24,25 This reaction is catalyzed by a mitochondrial NOS (mtNOS) with similar cofactor and substrate requirements as constitutive NOS, but mtNOS can cross-react with antibodies to inducible NOS (NOS2).²⁴ The ^•NO produced in mitochondria has direct actions in mitochondria.²⁴ NO at nanomolar concentrations can rapidly and reversibly inhibit mitochondrial respiration by nitration or nitrosylation.²⁵

B. Mitochondria and Ca²⁺ Buffering

There is a 10,000-fold Ca²⁺ concentration gradient across the cell membrane, which separates an extracellular 1mM Ca²⁺ concentration from an intracellular 50–100nM Ca²⁺ concentration.²⁶ Mitochondria function in the regulation of cytoplasmic Ca²⁺ levels.³ Utilizing specific transport systems, these organelles can move Ca²⁺ from the cytosol into their matrix by the Ca²⁺ uniporter and eject Ca²⁺ via the Na⁺/Ca²⁺ exchanger.³ Under conditions of elevated cytoplasmic Ca²⁺, whenever the local free Ca²⁺ concentration rises above a set-point of ≈0.5μM, mitochondria avidly accumulate Ca²⁺ to a fixed capacity.³ The inner mitochondrial membrane (IMM) potential, Δψ_m, provides the driving force for the accumulation of Ca²⁺ into the matrix. Cytosolic Ca²⁺ concentration above set-point levels is believed to be achieved during tetanic stimulation and glutamate receptor activation.³ In settings of excitotoxicity, resulting from excessive overstimulation of glutamate receptors, Ca²⁺ overload in neurons is significant. When mitochondria become overloaded with Ca²⁺, they undergo mPT resulting in osmotic swelling and rupture of the outer mitochondrial membrane (OMM). Mitochondria within synapses appear to be more susceptible than nonsynaptic mitochondria to Ca²⁺ overload.²⁷

C. Mitochondrial DNA

Each human cell contains hundreds of mitochondria and thousands of maternally inherited mtDNA copies residing in the matrix as double-stranded circular molecules of ≈16.5kb that contain 37 genes, all of which are transcribed.⁴ mtDNA encodes 12S and 16S rRNAs and the 22 tRNAs required for mitochondrial protein synthesis occurring at mitochondrial ribosomes. mtDNA also encodes 13 proteins that are structural subunits of oxidative phosphorylation enzyme complexes, including 7 of the 46 proteins of complex I (NADH dehydrogenase), 1 of the 11 proteins of complex III (bc₁ complex), 3 of the 13 proteins of complex IV (cytochrome c oxidase), and 2 of the 16 proteins of complex V (ATP synthase).⁴ Mitochondrial ROS can damage mtDNA, fostering the belief that mtDNA has a very high mutation rate.⁴ Cells containing a mixed population of normal and mutant mtDNA are known as heteroplasmic. In postmitotic tissues, mutant mtDNA can be preferentially, clonally amplified. One type of mtDNA mutation, called the ≈5kb common mtDNA deletion (mtDNA4977), is found nonuniformly within different areas of the aging human brain.^28,29

D. DNA Repair in Mitochondria

mtDNA sustains higher steady-state damage compared to nuclear DNA.⁴ This greater lesion accumulation might be caused by greater local levels of ROS and lack of chromatin protection afforded by histones. Active DNA base excision repair (BER) proteins, all encoded by nuclear DNA, are present in mitochondria,³⁰ although at lower levels than in nuclei. Nuclei and mitochondria use variant proteins for BER.³¹ Splice variants or truncation products of 8-oxoguanine DNA glycosylase-1 (OGG1), endonuclease III-like protein (NTH1), apurinic/apyrimidinic endonuclease (APE, also known as HAP1 and redox factor-1), and DNA ligase IIIβ are present in mitochondria.³¹ Import mechanisms for OGG1 into mitochondria may undergo age-related perturbations.³² DNA polymerase γ (POLG) is thought to be unique for mtDNA BER and replication. Human POLG is a nuclear-encoded gene product identified relatively recently,³³ and, since then, over 100 pathogenic mutations in POLG1 have been discovered to cause several neurological and nonneurological disorders.¹¹

E. Mitochondrial Trafficking and Cytoskeletal Motor Proteins for Mitochondria

Various cargos are transported over short and long distances along microtubule tracks within neurons and their processes.³⁴ In axons, mitochondria move in both directions and can also be stationary for long periods.³⁵ Most of the mitochondria in axons move relatively rapidly at rates of 0.5–0.7μm/s. Microtubules within axons are polarized, with their minus ends aligned toward the soma and their plus ends toward the synapse. Kinesin and dynein are directional molecular motors that are responsible for the fast transport of axonal mitochondria and vesicles.³⁴ Kinesin (a plus-end directed motor) moves mitochondria in the anterograde direction to the nerve terminal. Kinesin family members Kif1B and Kif5B are the motor proteins for anterograde movement of mitochondria.³⁶ Dynein (a minus-end directed motor) moves mitochondria in the retrograde direction to the soma. Cytoplasmic dynein is the primary motor for retrograde movement of mitochondria.³⁴ Mitochondrial movement may also occur on the actin cytoskeleton via myosin motors.³⁷

The transport of mitochondria responds to physiological changes in the cells. Stimulation of glutamate receptors, tau phosphorylation, NO signaling, and intracellular Ca²⁺ and Zn²⁺ accumulation can induce changes in mitochondrial movement and shape, which might or might not be related to mPT.^38,39 In cultured developing peripheral neurons, mitochondria undergo net anterograde movement and then move retrogradely from the distal axon when growth cone activity ceases.³⁵ Moreover, in developing axons, NGF application causes mitochondria to accumulate at sites of neurotrophin stimulation through a mechanism involving the phosphoinositide 3 (PI3)–kinase pathway.³⁵ Mitochondrial movements in cultured neurons can be blocked by drugs that depolymerize microtubules (nocodazole) or aggregate actin filaments (cytochalasin D).³⁷ New data show that axonal mitochondrial transport and potential are correlated. Drugs that inhibit mitochondrial function can either block anterograde transport of mitochondria or stimulate retrograde transport of mitochondria.⁴⁰ Cell culture studies also show that NO and Ca²⁺ can inhibit mitochondrial movement by disrupting cytoskeletal structures and inhibiting ATP synthesis, and Zn²⁺ can inhibit mitochondrial movement without depolarizing mitochondria.³⁹ Other experiments on cultured neurons show that phosphorylated tau regulates mitochondrial anterograde transport and that blocking tau phosphorylation by inhibition of glycogen synthase kinase-3β decreases anterograde transport of mitochondria, causing them to cluster in the cell body.⁴¹

III. Mitochondria and Cell Death

Cells can die by several different processes.^7,42,43 These processes have been classified canonically into two distinct categories, apoptosis and necrosis. These forms of cellular degeneration were classified originally as different because they appeared different microscopically (Fig. 2). Apoptosis is an orderly and compartmental dismantling of single cells or groups of cells, while necrosis is a lytic destruction of individual or groups of cells. Apoptosis is an example of PCD, which is an ATP-driven (sometimes gene transcription-requiring) form of cell suicide often committed by demolition enzymes called caspases (cysteinyl aspartate-specific proteinases), but other apoptotic and nonapoptotic caspase-independent forms of PCD exist.⁴³ Apoptotic PCD is instrumental in developmental organogenesis and histogenesis and adult tissue homeostasis, functioning to eliminate excess cells.⁴⁴ In healthy people, estimates reveal that between 50–70 billion cells in adults and 20–30 billion cells in a child between the ages of 8 and 14 die each day due to apoptosis.⁴⁴

A. Mitochondrial Regulation of Apoptosis

Apoptotic molecular networks are conserved in yeast, hydra, nematode, fruit fly, zebra fish, mouse, and human.⁴⁵ The current understanding of the molecular mechanisms of apoptosis in cells is built on studies by Robert Horvitz and colleagues on PCD in the nematode Caenorhabditis elegans.⁴⁶ They pioneered the understanding of the genetic control of developmental cell death by showing that it is regulated predominantly by three genes (C. elegans death, ced-3, ced-4, and ced-9).⁴⁶ This seminal work led to the identification of several families of apoptosis-regulation genes (Table I) in mammals, including the Bcl-2 family^47–49 and the caspase family of cysteine-containing, aspartate-specific proteases.⁵⁰ Other regulators of apoptotic cell death, most of which are mitochondrial proteins or influence mitochondria, are the p53 gene family, cell surface death receptors, cytochrome c, apoptosis-inducing factor (AIF), second mitochondrial derived activator of caspases (Smac), the inhibitor of apoptosis protein (IAP) family, and HtrA2/Omi.^51–57

TABLE I.

Some Mitochondrial Associated Cell Death Proteins and Their Actions

Protein	Function
Bcl-2^a	Anti-apoptotic, blocks Bax/Bak channel formation
Bcl-X_L	Anti-apoptotic, blocks Bax/Bak channel formation
Bax^a	Pro-apoptotic, forms pores for cytochrome c release
Bak^a	Pro-apoptotic, forms pores for cytochrome c release
Bad	Pro-apoptotic, decoy for Bcl-2/Bcl-X_L promoting Bax/Bak pore formation
Bid	Pro-apoptotic, decoy for Bcl-2/Bcl-X_L promoting Bax/Bak pore formation
Noxa	Pro-apoptotic, decoy for Bcl-2/Bcl-X_L promoting Bax/Bak pore formation
Puma	Pro-apoptotic, decoy for Bcl-2/Bcl-X_L promoting Bax/Bak pore formation
p53^a	Antagonizes activity of Bcl-2/Bcl-X_L, promotes Bax/Bak oligomerization
Cytochrome c	Activator of apoptosome
Smac/DIABLO	IAP inhibitor
AIF	Antioxidant flavoprotein/released from mitochondria to promote nuclear DNA fragmentation
Endonuclease G	Released from mitochondria to promote nuclear DNA fragmentation
HtrA2/Omi	IAP inhibitor
VDAC	mPTP component in outer mitochondrial membrane
ANT^b	mPTP component in inner mitochondrial membrane
Cyclophilin D^b	mPTP component in mitochondrial matrix
TSPO (peripheral benzodiazepine receptor)	Modulator of mPTP
Hexokinase	Modulator of VDAC

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Changes have been reported in human ALS.

A reported target of oxidative modification in mouse ALS.

Mitochondria have been identified as critical for the apoptotic process. In the seminal work by Xiaodong Wang and colleagues it was discovered that the mitochondrion integrates death signals engaged by proteins in the Bcl-2 family and releases pro-apoptotic molecules residing in the mitochondrial intermembrane space to activate caspases leading to internucleosomal cleavage of DNA (Figs. 1 and 3).^53,54 The endoplasmic reticulum (ER), which regulates intracellular Ca²⁺ levels, participates in a loop with mitochondria to modulate mitochondrial permeability and cytochrome c release through the actions of Bcl-2 protein family members (Fig. 1).⁵⁸

Fig 3 — Mitochrondrial regulation of apoptosis. Bcl-2 family members regulate apoptosis by modulating the release of cytochrome c. Bax and Bak are pro-apoptotic. They physically interact and form channels that are permeable to cytochrome c. BH3-only members (e.g., Bid, Noxa, Puma) are pro-apoptotic and can modulate the conformation of Bax. Bcl-2 and Bcl-X_L are anti-apoptotic and can block the function of Bax/Bak. The permeability transition pore (PTP), formed by the interaction of the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC) during the process of swelling, is a transmembrane channel that emerges at contact sites between the inner mitochondrial and the OMMs. The PTP has a role in regulating mitochondrial membrane potential and the release of cytochrome c. In the cytosol, cytochrome c, Apaf1, and procaspase-9 interact to form the apoptosome that drives the activation of caspase-3. The family of inhibitors of apoptosis (IAPs) blocks this process. The IAPs are inhibited by mitochondrially derived Smac, Diablo, and Omi. Caspase-3 cleaves many substrate proteins, some of which are endonucleases that translocate to the nucleus to cleave DNA into internucleosomal fragments (see DNA gel at lower right, showing molecular weight standards [M] in base pairs, developing rat cerebral cortex showing very low DNA fragmentation [lane 1], and developing rat brainstem inferior colliculus undergoing considerable apoptosis [lane 2]). Aif and endonuclease G are mitochondrially released proteins with nuclease activity that can translocate to the nucleus. Genomic DNA (double helix in nucleus) is the site of action of nucleases that induce strand nicks (X in helix). See text for detailed descriptions.

Bcl-2 family members regulate apoptosis by modulating the release of cytochrome c from mitochondria into the cytosol (Table I). Different models can account for this process: the Bcl-2-associated X protein (Bax)/Bcl-2-antagonist/killer 1 (Bak1) channel model and the mitochondrial apoptosis-induced channel (MAC) (Fig. 1). The bcl-2 proto-oncogene family is a large group of apoptosis regulatory genes encoding about 20 different proteins (Table I). These proteins are defined by at least one of the four conserved B-cell lymphoma (Bcl) homology domains (BH1–BH4) in their amino acid sequence that function in protein–protein interactions.^47–49 Some of the proteins (e.g., Bcl-2, Bcl-x_L, and Mcl-1) have all four BH1–BH4 domains and are anti-apoptotic (Table I). Other proteins that are pro-apoptotic have BH1–BH3 sequences (e.g., Bax and Bak1) or only the BH3 domain (e.g., Bad, Bid, Bim, Bik, Noxa, and Puma) that contains the critical death domain (Table I). Bcl-x_L and Bax have α-helices resembling the pore-forming subunit of diphtheria toxin⁵⁹; thus, Bcl-2 family members appear to function by conformation-induced insertion into the OMM to form channels or pores that can regulate the release of apoptogenic factors (Fig. 1).⁶⁰ Bcl-2 family members can form homo- or heterodimers and higher-order multimers with other family members.^47–49 Bax/Bak1 heterodimerization with either Bcl-2 or Bcl-x_L neutralizes their pro-apoptotic activity. When Bax and Bak1 are present in excess, the anti-apoptotic activity of Bcl-2 and Bcl-x_L is antagonized and apoptosis is promoted. In the Bax/Bak1 channel model (Fig. 1, left), after specific cell death-inducing stimuli, Bax undergoes a conformational change and translocates to the OMM where it inserts. Bak1 is a similar pro-apoptotic protein localized mostly to the OMM. Bax/Bak1 monomers physically interact to form oligomeric or heteromeric membrane channels that are permeable to cytochrome c.⁶⁰ The formation of these channels is blocked by Bcl-2 and Bcl-x_L at multiple sites. BH3-only members (Bad, Bid, Noxa, Puma) are pro-apoptotic and can modulate the conformation of Bax/Bak1 to sensitize this channel, possibly by exposing its membrane insertion domain, or they serve as decoys for Bcl-x_L that allow Bax to form pores in the OMM.⁶¹ Cells without bax and bak genes are resistant to mitochondrial cytochrome c release during apoptosis.⁶² Release of cytochrome c from mitochondria (Fig. 1) can occur through mechanisms that involve the formation of membrane channels comprising Bax and the voltage-dependent anion channel (VDAC).⁶³ The MAC could be a channel similar to the Bax/Bak1 channel, but it might also have additional components, such as VDAC.

Released cytochrome c then triggers the assembly of the cytoplasmic apoptosome (Figs. 1 and 3). The apoptosome is a protein complex of apoptotic protease activating factor 1 (Apaf1), cytochrome c, and procaspase-9. This is the engine that drives caspase-3 activation in mammalian cells (Figs. 1 and 3).⁵³ Caspases are cysteine proteases that have a near-absolute substrate requirement for aspartate in the P₁ position.⁶⁴ Fifteen caspase genes have been identified in mammals.⁶⁴ Caspases exist as constitutively expressed inactive pro-enzymes (30–50kDa) in healthy cells. Their zymogens are found in different proportions in different subcellular locations. In Henrietta Lacks (HeLa) cervical epithelial carcinoma cells, most caspase-3 pro-enzyme is found in the cytoplasm, while only 10% is found in mitochondria.⁶⁵ Ninety percent of caspase-9 pro-enzyme is mitochondrial in rat heart and brain.⁶⁶

So far, three caspase-related signaling pathways have been identified that can lead to apoptosis,^53,54,67,68 but cross talk among these pathways is possible. The intrinsic mitochondria-mediated pathway is controlled by Bcl-2 family proteins. It is regulated by cytochrome c release from mitochondria, promoting the activation of caspase-9 through Apaf1, and then caspase-3 activation (Figs. 1 and 3).^53,54 Apaf1 is a cytoplasmic protein that contains several copies of the WD-40 domain (≈40-amino acid motifs often terminating in a Trp-Asp dipeptide), a caspase recruitment domain, and an ATPase domain. Upon binding cytochrome c and dATP, Apaf1 forms an oligomeric apoptosome. The apoptosome binds and cleaves caspase 9 preproprotein (Apaf3), releasing its mature, activated form. Activated caspase 9 cleaves pro-caspase-3. The extrinsic death receptor pathway involves the activation of cell-surface death receptors, including Fas and the tumor necrosis factor receptor, leading to the formation of the death-inducing signaling complex and caspase-8 activation, which, in turn, cleaves and activates downstream caspases such as caspase-3, -6, and -7.⁶⁸ Caspase-8 can also cleave Bid leading to the translocation, oligomerization, and insertion of Bax or Bak1 into the mitochondrial membrane.⁶⁸ Another pathway involves the activation of caspase-2 by DNA damage or ER stress as a premitochondrial signal.⁶⁹

The activity of pro-apoptotic proteins is blocked to prevent untimely apoptosis in normal cells. Apoptosis can be antagonized by the IAP family in mammalian cells.^70–72 This family includes X chromosome-linked IAP (XIAP), IAP1, IAP2, neuronal apoptosis inhibitory protein, Survivin, Livin, and Apollon. These proteins are characterized by 1–3 baculoviral IAP repeat domains consisting of a zinc finger domain of ~70–80 amino acids.⁷¹ Apollon is a huge (530kDa) protein that also has a ubiquitin-conjugating enzyme domain. The main identified anti-apoptotic function of IAPs is the suppression of caspase activity.⁷² Procaspase-9 and -3 are major targets of several IAPs. IAPs reversibly interact directly with caspases to block substrate cleavage. Apollon also ubiquitinates and facilitates proteasomal degradation of active caspase-9 and second mitochondria-derived activator of caspases (Smac).⁷³

Mitochondrial proteins exist that inhibit mammalian IAPs. A murine mitochondrial protein called Smac and its human ortholog DIABLO (for direct IAP-binding protein with low pI) inactivate the anti-apoptotic actions of IAPs and thus exert pro-apoptotic actions.^74,75 Smac/DIABLO are released into the cytosol to inactivate the anti-apoptotic actions of IAPs that inhibit caspases (Figs. 1 and 3). These IAP inhibitors are 23kDa mitochondrial proteins (derived from 29kDa precursor proteins processed in the mitochondria) that are released into the cytosol from the intermembrane space to sequester IAPs. High-temperature requirement protein A2 (HtrA2), also called Omi, is another mitochondrial serine protease that exerts pro-apoptotic activity by inhibiting IAPs.⁷⁶ HtrA2/Omi functions as a homotrimeric protein that cleaves IAPs irreversibly, thus facilitating caspase activity. The intrinsic mitochondrial-mediated cell death pathway is regulated by Smac and HtrA2/Omi.⁷⁶ Mutations in the htra2 gene, identified as PARK13 (Table II), have been linked to the development of PD,⁷⁷ but this linkage is controversial.³⁷²

TABLE II.

Mutant Genes Linked to Familial PD

Locus	Inheritance	Gene	Protein name/function
PARK1/4q21	Autosomal dominant	α-Syn	α-Syn/presynaptic maintenance?
PARK2/6q25.2-27	Autosomal recessive	parkin	Parkin/ubiquitin E3 ligase
PARK3/2p13	Autosomal dominant	?	?
PARK44p15	Autosomal dominant	α-Syn	α-Syn/presynaptic maintenance?
PARK5/4p14	Autosomal dominant	UCHL1	UCHL1/polyubiquitin hydrolase
PARK6/1p36	Autosomal recessive	PINK1	PTEN-induced putative kinase-1/mitochondrial protein kinase
PARK7/1p36.33-36-12	Autosomal recessive	DJ-1	DJ-1/mitochondrial antioxidant, chaperone
PARK8/12q12	Autosomal dominant	LRRK2	Dardarin/multifunctional kinase/GTPase
PARK9/1p36	Autosomal recessive	ATP13A2	Lysosomal type 5 P-ATPase
PARK10/1p32		?	?
PARK11/2q36-37	Autosomal dominant	GIGYF2?	Grb10-interacting GYP protein 2, modulates tyrosine kinase receptor signaling, including IGF-1
PARK12/Xq21-q25	X-linked	?	?
PARK13/2p12	Autosomal recessive susceptibility factor	Omi/HtrA2	Omi/HtrA2, mitochondrial serine peptidase, inhibitor of IAPs
PARK14/22q13.1	Autosomal recessive	PLA2G6	Phospholipase A2 group VI
PARK15/22q12–q13	Autosomal recessive	FBXO7	F-box protein 7

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B. Apoptosis-Inducing Factor

AIF is a mammalian mitochondrial protein identified as a flavoprotein oxidoreductase.⁷⁸ AIF has an N-terminal mitochondrial localization signal that is cleaved off to generate a mature protein of 57kDa after import into the mitochondrial intermembrane space. Under normal physiological conditions, AIF might function as a ROS scavenger targeting H₂O₂⁵⁵ or in redox cycling with nicotinamide adenine dinucleotide phosphate.⁷⁹ After some apoptotic stimuli, AIF is released from mitochondria (Figs. 1 and 3) and translocates to the nucleus.⁷⁸ Overexpression of AIF in cultured cells induces cardinal features of apoptosis, including chromatin condensation, high-molecular-weight DNA fragmentation (Fig. 3), and loss of mitochondrial transmembrane potential.⁷⁸

C. Cell Death by Necrosis and the Mitochondrial Permeability Transition Pore

Cell death caused by cytoplasmic swelling, nuclear dissolution (karyolysis), and lysis has been classified traditionally as necrosis (Fig. 2).^80,81 Cell necrosis (sometimes termed oncosis)⁸¹ can result from rapid and severe failure to sustain cellular homeostasis, notably cell volume control.⁸² The process of necrosis involves damage to the structural and functional integrity of the cell plasma membrane and associated enzymes (e.g., Na⁺,K⁺-ATPase), abrupt influx and overload of ions (e.g., Na⁺ and Ca²⁺) and H₂O, and rapid mitochondrial damage and bioenergetic collapse.^83–85 Metabolic inhibition, anoxia, and oxidative stress from ROS can trigger necrosis. Inhibitory cross talk between ion pumps causes pro-necrotic effects when Na⁺,K⁺-ATPase “steals” ATP from the plasma membrane Ca²⁺ ATPase, contributing to Ca²⁺ overload and mitochondrial damage.⁸⁶

The morphology and some biochemical features of classic necrosis in neurons are distinctive (Fig. 2).^14,42 The main features are swelling and vacuolation/vesiculation of organelles (Fig. 2), destruction of membrane integrity, digestion of chromatin, and dissolution of the cell. The overall profile of the moribund cell is generally maintained as it degrades into the surrounding tissue parenchyma. The debris induces an inflammatory reaction in tissue. In necrosis, dying cells do not bud to form discrete membrane-bound fragments. The nuclear pyknosis and karyolysis appear as condensation of chromatin into many irregularly shaped small clumps, sharply contrasting with the formation of a few uniformly dense and regularly shaped chromatin aggregates that occur in apoptosis. In cells undergoing necrosis, genomic DNA is digested globally, because proteases that digest histones, which protect DNA, and DNases are coactivated to generate many randomly sized fragments seen as a DNA smear by gel electrophoresis (Fig. 2, right). These cytoplasmic and nuclear changes in pure necrosis are thought to be very diagnostic (Fig. 2).

Recent work has shown that cell necrosis in some settings is not as chaotic, random, and incomprehensible as envisioned originally but can involve the activation of specific signaling pathways to eventuate in cell death.^87–90 This idea is very important for developing new mechanism-based therapeutics to block cell necrosis.^16,17 For example, DNA damage can lead to poly(ADP-ribose) polymerase activation and ATP depletion, mitochondrial energetic collapse, and necrosis.⁹¹ Other pathways for “programmed” necrosis involve death receptor signaling through NADPH oxidase, receptor-interacting protein 1, and mitochondrial permeability transition (mPT) (Figs. 1 and 2).^{88–90,92,93}

mPT is a mitochondrial state in which the proton-motive force is disrupted reversibly or irreversibly.^{18–20,92–95} Conditions of intramitochondrial Ca²⁺ overload, excessive oxidative stress, and decreased electrochemical gradient (Δψ_m), ADP, and ATP can favor mPT. This altered condition of mitochondria involves the mPTP that functions as a voltage, thiol, and Ca²⁺ sensor.^{18–20,92–95} The mPTP is believed to be a poly-protein transmembrane channel (Fig. 1) formed at the contact sites between the OMM and the IMM. The collective components of the mPTP are still controversial. The VDAC (porin) in the OMM, the ANT (or solute carrier family 25) in the IMM, and cyclophilin D (CyPD) in the matrix at one time were believed to be the core components (Fig. 1 and Table I),^{18–20,92–95} but these proteins now seem to be dispensable for mPTP formation. Other components or modulators of the mPTP appear to be the mitochondrial phosphate carrier, hexokinase, creatine kinase, translocator protein 18kDa (TSPO, or peripheral benzodiazepine receptor), and Bcl-2 family members (Table I).⁹⁵

The VDAC family in human and mouse cells consists of three proteins of ≈31kDa (VDAC1–3) encoded by three different genes.⁹⁶ VDACs are the major transport proteins in the OMM, functioning in ATP rationing, Ca²⁺ homeostasis, oxidative stress response, and cell death.⁹⁶ Monomeric VDAC serves as the functional channel, although oligomerization of VDAC into dimers, tetramers, and higher-order multimers can occur and might function in cell death.⁹⁶ The VDAC adopts an open conformation at low or zero membrane potentials and a closed conformation at potentials above 30–40 mV.⁹⁶ In the open conformation, the VDAC makes the OMM permeable to most small hydrophilic molecules up to 1.3kDa for free exchange of respiratory chain substrates.⁹⁷ VDAC closure increases inward Ca²⁺ flux across the OMM^98,99 and causes oxidative stress.⁹⁹ Most data implicating VDAC opening or closing as an important regulator of cell death are based on in vitro conditions (cell culture and cell-free systems), while limited in vivo evidence is available.¹⁰⁰ VDAC1 binds Bak1, hexokinase, gelsolin, and ANT1/ANT2; VDAC2 binds Bak1, hexokinase, cytochrome c, glycerol kinase, and ANT1/ANT2; and VDAC3 binds glycerol kinase, CyPD, and ANT1-3.⁹⁶ In human tissues, VDAC1 and VDAC2 isoforms are expressed more abundantly than VDAC3. Highest levels are found in kidney, heart, skeletal muscle, and brain.¹⁰¹ The effects of selective knockout of VDAC isoforms are not equivalent, implying different functions. Mice deficient in either VDAC1 or VDAC3 are viable,^102–104 but VDAC2 deficiency causes embryonic lethality.¹⁰⁵ Lack of both VDAC1 and VDAC3 causes growth retardation.¹⁰⁴ VDAC null mouse tissues exhibit deficits in mitochondrial respiration and abnormalities in mitochondrial ultrastructure.¹⁰² However, mitochondria without VDAC1 have an intact mPT response.^106,107 VDAC2 deletion, but not lack of the more abundant VDAC1, results in enhanced activation of the mitochondrial apoptosis pathway and enforced activation of Bak1 in mitochondria,¹⁰⁵ consistent with the idea that VDAC2 is a key inhibitor of Bak1-mediated apoptosis.¹⁰⁴ However, other data show that cells lacking individual VDACs or combinations of VDACs have normal death responses to Bax and Bid.¹⁰⁷ Recent work in yeast has revealed that SOD1 is necessary for proper functioning of VDAC. Specifically, SOD1 regulates VDAC channel activity and protein levels in mitochondria.¹⁰⁸

The mitochondrial ANT family in humans consists of three members (ANT1–3, or solute carrier family 25, members 4–6) encoded by three different genes, but in mouse only two isoforms of the ANT are present.¹⁰⁹ The proteins are ≈33kDa in size and function as homodimers.¹⁰⁹ They are multipass membrane proteins, with odd-numbered transmembrane helices that mediate exchange of cytosolic ADP for mitochondrial ATP across the inner membrane utilizing the electrochemical gradient.¹¹⁰ These helices have kinks because of proline residues.¹¹⁰ ANT1 binds VDAC1, CyPD, Bax, twinkle (ataxin-8), and cyclophilin-40; ANT2 binds VDAC1–3 and cyclophilin-40; and ANT3 binds VDAC1, steroid sulfatase, and translocase of inner mitochondrial membrane-13 (TIMM13) and TIMM23.¹⁰⁹ The ANT isoforms are expressed differentially in tissue- and animal-specific patterns.¹¹¹ ANT1 is expressed highly in human and mouse heart and skeletal muscle. Human brain has low ANT1 mRNA but high ANT3 mRNA, while mouse brain has high ANT1 mRNA.¹¹¹ ANT2 mRNA is very low or not expressed in most adult human and mouse tissues, except kidney.¹¹¹ In tissue mitochondria in which more than one ANT isoform is expressed, it is ANT1 that binds preferentially to CyPD to form the mPTP at contact sites between the IMM and the OMM (Fig. 1).¹¹² It has been proposed that, in the presence of high mitochondrial Ca²⁺, the binding of CyPD to proline residue 61 (Pro⁶¹) in loop 1 of ANT1 results in a conformation that converts the ANT into a nonspecific pore.¹⁰⁹ Nonconditional ANT1 null mice are viable and grow normally but develop mitochondrial skeletal myopathy and cardiomyopathy.¹¹⁰ Ablation of both ANT isoforms in mouse liver surprisingly did not change fundamentally mPT and cell death in hepatocytes,¹¹³ and some ANT ligands induced mitochondrial dysfunction and cytochrome c release independent of mPT.¹¹⁴ Clearly, the mechanisms of ANT-mediated cell death need further study.

CyPD (also named cyclophilin F, peptidyl prolyl isomerase F) is encoded by a single gene.^17,90 There is only one isoform of CyPD (EC 5.2.1.8, ppif gene product) in mouse and human. The ≈20kDa protein encoded by this gene is a member of the peptidyl-prolyl cis–trans isomerase (PPIase) family. PPIases catalyze the cis–trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. CyPD binds ANT1.¹⁰⁹

During normal mitochondrial function, the OMM and the IMM are separated by the intermembrane space, and the VDAC and the ANT do not interact.^93–95 Permeability transition is activated by the formation of the mPTP (Fig. 1). The IMM loses its integrity and the ANT changes its conformation from its native state into a nonselective pore.¹⁰⁹ This process is catalyzed by CyPD functioning as a protein cis–trans isomerase and chaperone.¹⁷ The ANT and CyPD interact directly in this process.¹¹⁵ The amount of CyPD (in heart mitochondria) is much lower than the ANT concentration (<5%); thus, under normal conditions, only a minor fraction of the ANT can be in a complex with CyPD.^115,116 When this occurs, small ions and metabolites permeate freely across the IMM and oxidation of metabolites by O₂ proceeds with electron flux not coupled to proton pumping, resulting in collapse of Δψ_m, dissipation of ATP production, elevated production of ROS, equilibration of ions between the matrix and the cytosol, increased matrix volume, and mitochondrial swelling.⁹⁴

Very few studies have been published on the localizations of putative mPTP components in the mammalian central nervous system (CNS), and therefore details about cellular expression in different nervous system cell types are lacking. VDAC expression patterns are complicated by alternative splicing that generates two different VDAC1 mRNAs, three different VDAC2 mRNAs, and two different VDAC3 mRNAs.⁹⁶ Studies of nervous tissue have found VDAC in neurons and glial cells¹¹⁷ and associated with mitochondria, the ER, and the plasma membrane.^118,119 Nonmitochondrial localizations of VDAC have been disputed.¹²⁰ Information on the cellular localizations of ANT in nervous tissue is scarce. ANT appears to be expressed in reactive astrocytes.¹²¹ The few published studies on CyPD localization in mammalian CNS have found it enriched in subsets of neurons in adult rat brain, with some interneurons being positive¹²² but astrocytes having relatively low levels.¹²³ In mouse spinal cord, putative components of the mPTP (VDAC, ANT, and CyPD) are enriched in motor neurons, as determined by immunohistochemistry.¹²⁴ The specific isoforms of ANT and VDAC in motor neurons have not been determined. CyPD, ANT, and VDAC have mitochondrial and nonmitochondrial localizations in motor neurons.¹²⁴ They are all nuclear-encoded mitochondrial-targeted proteins, thus a possible explanation for their nonmitochondrial localizations is that they are premitochondrial forms. Some cyclophilins are located in the cytoplasm,¹²⁵ such as cyclophilin A, but CyPD immunoreactivity is not observed in ppif^–/– mice, demonstrating that the antibody is detecting only CyPD.¹²⁴ Spinal cord, brainstem, and forebrain had similar levels of CyPD, as well as similar levels of ANT and VDAC.¹²⁴ Thus, differences in the levels of individual mPTP components cannot explain the intrinsic differences in the sensitivity to Ca²⁺-induced mPT seen in isolated mitochondria from spinal cord and brain.^126,127 Not all mitochondria within individual motor neurons contain CyPD, ANT, and VDAC.¹²⁴ This observation supports the idea that mitochondria in individual cells are not only heterogeneous in shape^128,129 but also in biochemical composition, metabolism,¹³⁰ and genetics.⁴

IV. Mitochondrial Autophagy

Autophagy is a mechanism whereby eukaryotic cells degrade their own cytoplasm and organelles.¹³¹ Autophagy functions as a homeostatic nonlethal stress response mechanism for recycling proteins to protect cells from low supplies of nutrients and as a cell death mechanism.¹³¹ Mitochondrial removal is mediated by autophagy. Nutrient and neurotrophin withdrawal can elicit mitochondrial autophagy in cultured neurons.¹³² Degradation of mitochondria by autophagy can occur during death of neurons in culture.^132,133 In in vivo axotomy/target deprivation models, injured neurons can survive for months with a striking paucity of mitochondria within the cell body.^134,135 It is possible that some neurons might remove altered or injured mitochondria as part of their survival mechanisms either for eliminating toxic molecules or organelles or for scavenging nutrients. In contrast, neurons that die from axotomy accumulate mitochondria pre-apoptotically.^136,137 Spinal interneurons dying apoptotically after an excitotoxic insult also accumulate mitochondria pre-apoptotically.¹³⁸

Autophagy is also called Type II PCD.¹³⁹ This degradation of organelles and long-lived proteins is carried out by the lysosomal system. A hallmark of autophagy thus is the accumulation of autophagic vacuoles of lysosomal origin. Autophagy has been seen in developmental and pathological conditions. For example, insect metamorphosis involves autophagy⁴³ and developing neurons can use autophagy as a PCD mechanism.^140,141 Degeneration of Purkinje neurons in the mouse mutant Lucher appears to be a form of autophagy, thus linking excitotoxic constitutive activation of the GluRδ2 glutamate receptor to autophagic cell death.¹⁴² However, loss of basal autophagic function in the CNS causes neurodegeneration in mice.^143,144 This finding could be a testimonial to the importance of Parkin, a ubiquitin kinase encoded by Parkinson's disease-related PARK2, which functions to promote autophagic turnover of mitochondria.¹⁴⁵

The molecular controls of autophagy appear common in eukaryotic cells from yeast to human, and autophagy may have evolved before apoptosis.¹⁴⁶ However, much work has been done on yeast, while detailed work on autophagy in mammalian cells is emerging.¹⁴⁷ Double-membrane autophagosomes for sequestration of cytoplasmic components are derived from the ER or the plasma membrane. Tor kinase, PI3-kinase (a family of cysteine proteases called autophagins), and death-associated proteins function in autophagy.^148,149 Autophagic and apoptotic cell death pathways cross-talk. The product of the tumor suppressor gene Beclin1 (the human homolog of the yeast autophagy gene APG6) interacts with the anti-apoptosis regulator Bcl-2.¹⁵⁰ Autophagy can block apoptosis by sequestration of mitochondria. If the capacity for autophagy is reduced, stressed cells die by apoptosis, whereas inhibition or blockade of molecules that function in apoptosis can convert the cell death process into autophagy.¹⁵¹ Thus, a continuum between autophagy and apoptosis could exist.

V. Mitochondrial Fission and Fusion

Mitochondria are not static organelles. They can undergo cycles of fusion and fission, and the balance of these events in part determines mitochondrial morphology. Mitochondrial fusion and fission events are controlled by several proteins, including dynamin-like proteins (Mfns and OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission protein 1 (Fis1).^9,152

Mfn1, Mfn2, and OPA1 are mitochondrial GTPases essential for mitochondrial fusion.⁹ Mfns and OPA1, residing in the OMM and intermembrane space, respectively, promote mitochondrial fusion. Mfn1 and Mfn2 can homodimerize and heterodimerize, but Mfns and OPA1 appear not to interact biochemically in mammalian cells. Mfns possess a C-terminal coiled-coil domain that mediates oligomerization between Mfn molecules on adjacent mitochondria. OPA1 forms oligomeric complexes consisting of membrane-bound and soluble forms of OPA1 and may form a diffusion barrier for proteins stored in mitochondrial cristae.⁹ OPA1 also functions in apoptosis. Proteolytic processing in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release cytochrome c into the mitochondrial intermembrane space.

New mitochondria are generated by fission, which is controlled by at least two proteins (Fis1 and Drp1).⁹ Fis1 is a single-pass transmembrane protein that is anchored to the OMM. Fis1 can weakly bind Drp1. In contrast, Drp1 is present mostly in the cytoplasm but a portion localizes to puncta on the mitochondria surface. It has been postulated that bound Drp1 at the mitochondrial surface couples GTP hydrolysis to mitochondrial membrane constriction and fission. Mitochondrial fission might even be an important part of the mechanisms driving cell death because inhibition of Drp1 function blocks apoptosis in nonneuronal cell lines. Under stress conditions, Drp1 translocates to mitochondria and localizes to scission foci.¹⁵³ Mitochondrial fission appears to involve Bax, because Bax translocates to scission foci as well.¹⁵³ It is believed that most mitochondriogenesis occurs in the perinuclear region.¹⁵⁴ NO can stimulate mitochondrial biogenesis.¹⁵⁵

VI. Mitochondrial Involvement in Adult-Onset Neurodegenerative Diseases

A. Alzheimer's Disease

AD is the most common cause of dementia occurring in middle and late life.¹⁵⁶ Population-based surveys estimate that AD affects 7–10% of individuals >65 years of age and possibly 50–60% of people over 85 years of age.^157,158 AD now affects about 2% of the population, or about 4million people in the United States and ~35 million people worldwide.¹⁵⁹ The prevalence of AD is increasing proportionally to increased life expectancy, and estimates predict that the prevalence will reach ~107 million by 2050.¹⁶⁰

Most cases of AD have late-onset and unknown etiologies and are termed “sporadic.” However, some cases, particularly those with early onset, are familial and are inherited as autosomal-dominant disorders linked to mutations in the gene that encodes the amyloid precursor protein (APP)^161–164 or genes that encode presenilin proteins.^165,166 For late-onset sporadic cases, a variety of risk factors have been identified.¹⁶⁷ Aging is the strongest risk factor.¹⁶⁷ The apolipoprotein E (APOE) gene is a susceptibility locus, with the APOE ε4 allele showing dose-dependent contributions to AD risk.¹⁶⁸ Cardiovascular disease and head trauma are additional risk factors for AD.¹⁵⁶

The dementia in AD is caused by severe atrophy of the forebrain. Neurons in the neocortex, hippocampus, and basal forebrain are selectively vulnerable in AD.^169–173 The numerous lesions that are formed in the brains of AD patients are termed senile plaques, which are abnormal extracellular deposits of amyloid β-protein (Aβ), and neurofibrillary tangles (NFTs), which are abnormal intracellular aggregates of protein containing hyperphosphorylated tau (a microtubule-associated protein).^174,175

The mechanisms of neuronal degeneration AD are not known, and existing information is incomplete. Abnormal processing or modification of APP and the cytoskeletal protein tau are involved (Fig. 4).¹⁷⁶ Cortical and hippocampal neuronal degeneration could be the consequence of a combination of several mechanisms, including perturbations in protein metabolism, excitotoxicity, oxidative stress, mitochondrial perturbations, and inflammation. The possible specific mechanisms for neuronal degeneration in AD may involve dysfunction of N-methyl-d-aspartate receptors,^177,178 dysregulation of Ca²⁺ and mitochondrial homeostasis,^179,180 defects in synapses,^181–185 abnormalities in the metabolism of APP and presenilin proteins, toxic actions of Aβ,^185–187 and cytoskeletal pathology linked to abnormal phosphorylation.^188,189

Fig 4 — Brain atrophy and neurodegeneration in AD. Midsagittal views (center pictures) of the brains from an 85-year-old individual with AD and an 86-year-old normal individual. The microscopic neuropathological hallmarks of AD are senile plaques (scale bar=200μm), and neurofibrillary tangles (NFTs, scale bar=50μm) The silver stain detects deposits and accumulations of abnormal proteins such as a amyloid beta protein-containing senile plaques (open arrows) in cerebral cortex (top left image) and NFTs in neurons and neuronal tombstones (open arrows, top middle image). Antibodies can be used to detect protein constituents of NFTs in neurons such a hyperphosphorylated tau (open arrows in top right image). These abnormalities are microscopic pathological entities associated with AD.

There are possible disease links between intraneuronal Aβ and mitochondria, suggesting an intracellular toxic activity of Aβ.^190–192 Importantly, APP possesses a targeting sequence for mitochondria.¹⁹⁰ When overexpressed in cultured cells, APP interacts with mitochondrial import proteins, can arrest mitochondrial import, and can result in bioenergetic deficits.¹⁹⁰ In postmortem human brain samples, APP variants were found to be associated with mitochondria from the AD brain, but not mitochondria from control brain,^21,191 and APP can interact with the translocase of the outer mitochondrial membrane (TOMM40) and TIMM23.¹⁹¹ The human AD autopsy brain shows evidence for mitochondrial impairments.¹⁸⁰ High mitochondrial APP levels mirror abnormalities in respiratory chain subunit levels and activity and enhanced ROS production.¹⁹¹ Aβ can interact with the mitochondrial matrix protein Aβ-binding alcohol dehydrogenase in human AD brain and is believed to participate in mitochondrial dysfunction and oxidative stress.¹⁹³ A possible intraneuronal Aβ-mitochondria link was shown by electron microscopy (EM) in aged nonhuman primate neocortex.¹⁸³

In an APP transgenic (tg) mouse line (Tg2576), Aβ was also found to associate with mitochondria isolated from cerebral cortex.¹⁹² It has also been reported that Aβ interacts with CyPD in mouse and human cerebral cortex mitochondria to potentiate synaptic stress.¹⁹⁴ Genetic deletion of the ppif gene (CyPD knockout) in human mutant APP tg mice (J-20 line) protected neurons from Aβ- and oxidative stress-induced cell death.¹⁹⁴ However, these abnormalities might not be related to mPTP-driven cell death because these mice, and most other mouse models of AD, show scant or modest evidence for neurodegeneration resulting in neuronal cell death, despite tremendous brain burdens of Aβ.¹⁹⁵

B. Parkinson's Disease

PD is a chronically progressive, age-related, incapacitating movement disorder in humans. Estimates indicate that 4–6 million people have been diagnosed with PD and that ≈2% of the population will suffer from the disease at some time in life. The greatest prevalence occurs in the United States (100–250 cases per 100,000),¹⁹⁶ making PD as the second most common adult-onset neurodegenerative disease after AD. Most PD cases are sporadic (no known gene defects). However, some cases, particularly those with early onset, are familial (genetic) (Table II). Parkinsonism can be acquired from trauma and can be part of more global degenerative syndromes affecting multiple systems with features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies (LBs). Primary PD patients develop progressive resting tremor (4–7Hz), rigidity (stiffness), bradykinesia (slowing of movement), akinesia, gait disturbance, and postural instability.¹⁹⁷ The disease progression is also associated with mood disturbances, dementia, sleep disturbances, and autonomic dysfunction.¹⁹⁷ There are currently no cures for PD. Medications and neurosurgery can relieve some of the symptoms.

A major neuropathological feature of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and in other brainstem regions, which causes the movement disorder.¹⁹⁸ However, PD should be regarded as a multiregional, multisystem neurodegenerative disorder in which the pathology appears in a regionally specific sequence, beginning in the dorsal motor nucleus of the vagus and olfactory bulbs and anterior nucleus followed by the locus coeruleus and then the SNpc, at which time (when ≈50–70% of SNpc neurons are lost) a clinical diagnosis of PD becomes possible.¹⁹⁹ The movement disorder in PD is thought to arise from reduced dopaminergic innervation of the striatum resulting from the loss of SNpc neurons.¹⁹⁸ The effect of reduced dopaminergic input is overactivity of striatal neurons that project to, and inhibit, neurons in external globus pallidus (GPe), thereby reducing the normal GPe inhibition of excitatory subthalamic neurons.²⁰⁰ In addition, due to actions of dopamine on different dopamine receptor subtypes, there is also loss of normal dopaminergic excitation of striatal neurons that innervate the internal GP (GPi) and SN reticularis, causing increased γ-aminobutyric acidergic inhibition of thalamic nuclei that drive activation of cerebral cortex (Fig. 5).¹⁹⁸ The dopaminergic deficit in PD thus functionally translates to overactivity of the subthalamic nucleus and GPi.¹⁹⁸

Another neuropathological feature of PD is eosinophilic proteinaceous intraneuronal or intraglial inclusions, known as LBs (Fig. 5A). LBs are comprised of a dense core of filamentous material enshrouded by filaments that are 10–20 nm in diameter that contain ubiquitin and α-synuclein (α-syn).²⁰¹ It is not clear if LBs are related causally to the disease process or are consequences of it.

The molecular pathogenesis of PD is still not understood. Epidemiological studies reveal several risk factors for developing idiopathic PD, in addition to aging. Pesticides now have been linked convincingly to the development of PD.²⁰² Herbicides, well water (contaminated with pesticides), and industrial chemicals are possible neurotoxic agents related to the development of PD.²⁰³ It has been believed for over a decade that mitochondrial dysfunction is related to the pathogenesis of PD. Complex I activity was found to be reduced in the SNpc and platelets of PD cases, but changes in skeletal muscle remain contentious.²⁰³ Complex I inhibitors, notably rotenone, cause damage to dopaminergic neurons in animal models.²⁰⁴

C. Gene Mutations that Cause Some Forms of PD

About 5–10% of PD patients suffer a genetic (familial) form of the disease.²⁰³ Gene mutations with autosomal-dominant or autosomal-recessive inheritance patterns have been identified (Table II). PD-linked mutations occur in the genes encoding α-syn, Parkin, ubiquitin carboxy-terminal hydrolyase-L1 (UCHL1), phosphatase and tensin homolog-induced putative kinase-1 (PINK1), DJ-1, and leucine-rich repeat kinase-2 (LRRK2). In rare autosomal-dominant inherited forms of PD, missense mutations in the α-syn gene (PARK1) result in the amino acid substitutions Ala-53→Thr, Ala-30→Pro, or Glu-46→Lys. In addition, duplication and triplication mutations in the α-syn gene (PARK4) have been found.^205,206 A missense mutation in the UCHL1 gene (PARK5), resulting in the amino acid substitution Ile-93→Met, can also cause very rare autosomal-dominant PD.²⁰⁷ Loss-of-function mutations due to large deletions and truncations, and also missense or nonsense mutations, in parkin (PARK2), PINK1 (PARK6), and DJ-1 (PARK7) cause autosomal-recessive PD.^208–211 The more commonly occurring autosomal-dominant, and possibly sporadic, PD are caused by several missense mutations in the LRRK2 gene (PARK8), resulting in amino acid substitutions Tyr-1654→Cys, Arg-1396→Gly, Tyr-1699→Cys, Arg-1441→Cys, Ile-1122→Val, or Ile-2020→Thr.^212,213PARK9 has been ascribed to a deletion mutation (cytosine at nucleotide position 3057) or a guanine-toadenine transversion at a splice site of exon 13 in the ATP13A2 gene that encodes a predominantly neuronal P-type lysosomal ATPase.²¹⁴ Potential lysosomal dysfunction related to ATP13A2 mutant proteins might tie into PD etiology through abnormalities in autophagy. Mutations of genes at other PD loci are more controversial (Table II).

1. α-Synuclein

α-Syn is a relatively small (140 amino acids), very abundant (~1% of total protein) protein found in cells throughout the nervous system and is particularly enriched in axon terminals.^215–217 The functions of α-syn are not entirely understood. However, growing evidence supports a role for α-syn in neurotransmitter release. Mice without α-syn have no overt phenotype,²¹⁸ but neurons deficient in α-syn have a reduction in the reserve pool of synaptic vesicles needed for responses to tetanic stimulation and show defective mobilization of dopamine and glutamate.^217,219 Without α-syn, neurons have impaired, long-lasting enhancement of evoked and miniature neurotransmitter release.²²⁰ α-Syn is highly mobile and rapidly dissociates from synaptic vesicle membranes after fusion in response to neuronal activity.²²¹ α-Syn appears to function as a molecular chaperone to assist cysteine-string protein-α in the folding and refolding of SNARE synaptic proteins.^222,373,374

α-Syn is a soluble monomeric protein that can associate with mitochondrial membranes.²²³ α-Syn can undergo α-helix→β-sheet conformational transition, which leads to fibril formation.²²⁴ α-Syn is a major structural component of LBs, forming the ≈10-nm fibrils, but in most neurodegenerative diseases LBs are associated with accumulation of wild-type, not mutant, α-syn.²⁰¹ α-Syn mutations cause increased levels of protofibrils, possibly the more toxic form of the protein.²²⁵ α-Syn protofibrils might also be toxic by making membranes of cells more porous.²²⁶ Overexpression of human wild-type or mutant α-syn in cultured cells elevates the generation of intracellular ROS^227,228 and causes mitochondrial deficits.²²⁷ Moreover, expression of mutant α-syn increases cytotoxicity to dopamine oxidation products.²²⁹ Aggregation of wild-type and mutated α-syn is associated with enhanced cell death in cultured cells.²³⁰ Nitration of α-syn, signifying the presence of potent reactive nitrogen species such as peroxynitrate (ONOO^–), or its free-radical derivative nitrogen dioxide (^•NO₂), is a major signature of human PD and other synuclinopathies and might be critical to the aggregation process.^231,232

2. UCHL1 and Parkin

UCHL1 is a very abundant protein (~1–2% total soluble protein in brain) that functions in the formation and recycling of ubiquitin monomers for the ubiquitin–proteasome pathway.²³³ This pathway is important for intracellular protein turnover and degradation and functions generally in quality control of proteins in cells to eliminate misfolded, mutated, and damaged proteins.²³⁴ Ubiquitin is an abundant, small (≈8.5kDa) protein that is attached covalently to lysine aliphatic chains in proteins to mark them for degradation carried out by the 26S proteasome. UCHL1 hydrolyses the C-terminus of fusion proteins containing polyubiquitin molecules and ribosomal protein, thereby generating ubiquitin monomers. In vitro, PD-linked mutant UCHL1 has reduced enzyme activity,²³⁵ and inhibition of UCHL1 is associated with production of α-syn aggregates,²³⁶ indicating that α-syn can be degraded by the proteasome.

The ubiquitination of proteins is catalyzed by the activities of three enzymes called ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3).²³⁴PARK2, encoding parkin, which is a ubiquitin E3 ligase, causes juvenile-onset recessive PD (before 40 years of age)²¹⁰ with relatively confined neuronal loss in the SNpc and locus coeruleus, but with an absence of LBs. Several substrates of parkin have been identified, including α-syn, synphilin-1, and other synaptic proteins.²³⁷ Mutations in the PARK2 result in loss of function of E3, thereby possibly causing some substrates of parkin to accumulate and aggregate within cells. One parkin mutation found in a Turkish patient (Gln-311→X), replacing a glutamine residue at position 311 with a stop codon, causes a C-terminal truncation of 155 amino acids of Parkin.²³⁸

3. PINK1

The PARK6 locus contains the PINK1 gene.^209,211PARK6 kindreds have juvenile-onset PD and truncation mutations, missense mutations (His-271→Gln; Gly-309→Ala; Leu-347→Pro; Glu-417→Gly; Arg-246→X where X is any other amino acid; Trp-437→X), or compound nonsense mutations (Gln-309→X/Arg-492→X).

PINK1 is a 581-amino acid protein (≈63kDa) that contains a domain highly homologous to the serine/threonine protein kinases of the calcium/calmodulin family, and a mitochondrial targeting motif.²¹¹ Thus, PINK1 is a mitochondrial kinase. It is processed at the N-terminus in a manner consistent with mitochondrial import, but the mature protein is also present in the cytosol.²³⁹ Both human wild-type and mutant PINK1 localize to mitochondria.²⁴⁰ Interestingly, most of the reported mutations are in the putative kinase domain. PINK1 is expressed in many adult human tissues.²⁴¹ In adult rodents, PINK1 is expressed throughout the brain.²⁴² It is unclear how PINK1 mutations cause the selective death of SNpc neurons in human PD (Fig. 5). PINK1 appears to function in mitochondrial trafficking by forming a multiprotein complex with the GTPase Miro and the adaptor protein Milton.²⁴³ PINK1 may protect human dopaminergic neuroblastoma cells (SH-SY5Y) against mitochondrial malfunction under conditions of cell stress.²⁴⁴ In rat neuroblastoma cells, mutant PINK1 can induce abnormalities in mitochondrial Ca²⁺ influx and aggravate the cytopathology caused by mutant α-syn in a mechanism that involves the mPTP (Fig. 1).²⁴⁵

4. DJ-1

The PARK7 locus contains the DJ-1 gene.²⁰⁸PARK7 kindreds can have homozygous deletion of a large region within the DJ-1 gene causing complete loss of DJ-1 expression or homozygous missense mutations in the DJ-1 gene resulting in single amino acid substitutions in the DJ-1 molecule (Met-26→Ile, Glu-64→Asp, Leu-166→Pro).²⁰⁸

DJ-1 is a small (189-amino acid, ~20–25kDa) protein with multiple apparent functions involving cellular transformation, male fertility, control of protein–RNA interaction, and oxidative stress response.²⁰⁸ The protein exists in vivo as a dimer.²⁴⁶ DJ-1 is expressed throughout the mouse nervous system,²⁴⁷ where it might act as a neuroprotective intracellular redox sensor that can localize to the cytoplasmic side of mitochondria.²⁴⁸ The localization of DJ-1 to mitochondria is associated with protective actions against some mitochondrial poisons.²⁴⁸ Some DJ-1 mutant proteins have abnormalities in dimer formation and decreased stability.^249,250 It remains to be determined how mutated DJ-1 proteins trigger the degeneration of SNpc neurons in human PD (Fig. 5).

5. LRRK2

The PARK8 locus contains the LRRK2 gene.^212,213 Mutations in this gene are, to date, the most common in both familial and sporadic PD. The LRRK2 protein is a large multidomain protein (2527 amino acids, 286 kDa), also called dardarin (derived from the Basque word dardara, meaning tremor), that is expressed throughout the body.^212,213 Currently, it is not evident how PARK8 mutations relate to the selective death of neurons that causes human PD (Fig. 5). LRRK2 contains leucine-rich repeat domains, a Ras/small GTPase domain, a nonreceptor tyrosine kinase-like domain, and a WD-40 domain, consistent with the architecture of multifunctional Ras/GTPases of the Ras of complex family.^212,213 The presence of leucine-rich and WD40 domains suggests that LRRK2 is capable of multiple protein–protein interactions. The GTPase activity indicates that LRRK2 functions as a molecular switch, possibly involved in cytoskeleton organization and vesicle trafficking. The kinase domain may belong to the mitogen-activated protein kinase kinase kinase (MAPKKK or MEKK) family of kinases. Studies of rodent brain show little or no expression of LRRK2 in SNpc neurons.^251,252 However, expression of LRRK2 is high in dopamine-innervated brain regions.²⁵¹ Recent work shows that LRRK2 can influence mitochondrial- and death receptor-mediated cell death in cultured cells.^253,254 These findings might be hints that the target of SNpc neurons (i.e., the striatum) and SNpc neuron target deprivation are important to the understanding of pathogenic mechanisms of PD (Fig. 5).

D. PD α-Syn Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death

Identification of human genes linked to familial PD by molecular genetics drives experimental work on the generation of animal and cell models of PD. Parkin^–/– null mice have a normal lifespan, do not develop any major neurological abnormalities, have no loss of midbrain dopaminergic neurons, and do not form intracellular inclusions.^255,256 However, these mice exhibit modest evidence of dopaminergic presynaptic dysfunction in striatum and possible deficits in behavioral tests indicative of nigrostriatal dysfunction,²⁵⁵ although this finding has not been confirmed in another mouse line.²⁵⁶ Parkin^–/– mice show decrease in proteins involved in mitochondrial oxidative phosphorylation and oxidative stress in ventral midbrain and exhibit reduced mitochondrial respiration in striatum, but they have no mitochondrial ultrastructural abnormalities.²⁵⁷ Mice with null mutations in DJ-1 also have a normal lifespan and do not develop an overt phenotype or loss of dopaminergic neurons, but behavioral tests reveal age-dependent motor deficits and neurochemical assessments show altered striatal dopamine content.²⁵⁸ DJ-1 null mice also show altered D2 dopamine receptor-mediated function.²⁵⁹ In contrast, transgenic mice expressing the Parkin Q311X truncation mutation develop a progressive hypokinetic disorder, degeneration of SNpc neurons, and loss of striatal dopamine.²⁶⁰ Thus, Parkin could be important for maintenance of mitochondrial function or mitochondrial turnover through autophagy and synaptic integrity distally within the SNpc neuron target region.

Several tg mouse lines have been made using a variety of different promoters to drive expression of human full-length wild-type or mutant α-syn.^{230,261–266} Of these lines, mice expressing human A53T mutant α-syn have a shortened lifespan and develop a severe movement disorder and synucleinopathy.^230,263,266 It is noteworthy that there have been no reports of robust dopamine SNpc neuron degeneration in full-length α-syn tg mice or in any other tg or null mouse models of PD-linked genes. However, tg mice expressing a truncation mutant of human α-syn have an abnormal development-related loss of SNpc neurons.²⁶⁷ Cell death mechanisms or thresholds for cell death activation in human and mouse brain dopamine neurons might differ.

α-Syn tg mice do develop extensive cell death and neuronal loss in other regions of brain and in spinal cord.²⁶⁸ These tg mice express high levels of human wild-type or mutant (A53T and A30P) α-syn under the control of the mouse prion protein promoter.²⁶³ Mice expressing A53T α-syn (lines G2-3 and H5), but not mice expressing wild-type (line I2-2) or A30P (line O2) α-syn, develop adult-onset progressive motor deficits, including reduced spontaneous activity with bradykinesia, mild ataxia, and dystonia at ≈10–15 months of age, followed by rapidly progressive paralysis and death.²⁶³ A53T mice develop intraneuronal inclusions, mitochondrial degeneration, and cell death in neocortex, brainstem, and spinal cord.²⁶⁸ Brainstem neurons and spinal motor neurons display a prominent chromatolysis reaction and axonal spheroids,²⁶⁸ typical of that seen after axonal injury.²⁶⁹ A53T mice form LB-like inclusions in neocortical and spinal motor neurons and have progressive profound loss (≈75%) of motor neurons that causes their paralysis.²⁶⁸ Motor neuron loss in A53T mice has been shown by another group.²²²

Mitochondrial pathology in A53T mice involving mtDNA damage is seen frequently in the absence of nuclear DNA damage in large brainstem neurons and spinal motor neurons.²⁶⁸ Subsets of mitochondria in brainstem and spinal cord cells in A53T mice appear dysmorphic, becoming shrunken, swollen, or vacuolated.²⁶⁸ Human α-syn is found bound to some mitochondria in degenerating neurons in A53T mice.²⁶⁸ Some abnormal intracellular inclusions in these cells are degenerating mitochondria. A mitochondrial defect in A53T mice is further indicated by biochemical evidence revealing loss of complex IV activity.²⁶⁸

The mechanisms for this mtDNA damage may be related to oxidative stress, which is suggested by evidence that mitochondrial associated metabolic proteins are oxidized in A30P mice.²⁷⁰ α-Syn can generate H₂O₂²⁷¹ and ^•OH²²⁹in vitro upon incubation with Fe(II). Evidence for ONOO^–-mediated oxidative/nitrative stress in A53T mouse motor neurons has come from the observation of nitrated human synuclein.²⁶⁸ Nitrated synuclein formed inclusions in motor neurons consistent with in vitro data showing that ONOO^– promotes the formation of stable α-syn oligomers.^272,273 Our data showing mtDNA damage is in line with the presence of ONOO^– or its derivatives near mitochondria, because ONOO^– or products of ONOO^– are directly genotoxic by causing single- and double-strand breaks in DNA.²³ Moreover, the loss of complex IV enzyme activity without a change in protein level²⁶⁸ might be explained by inactivation of this mitochondrial enzyme by nitration. Overall, ONOO^–-mediated damage in mitochondria may be a key pathological mechanism leading to motor neuron degeneration in A53T mice.

The reasons for the vulnerability of mouse motor neurons to human A53T mutant α-syn are not clear. These mice express high levels of mRNA and protein for human α-syn in the forebrain, diencephalon, and midbrain,²⁶³ but these regions are much less vulnerable than spinal cord. A53T α-syn causes axonopathy^230,266; thus motor neuron vulnerability could be related to their long myelinated axons and interactions with oligodendrocytes and Schwann cells for myelin support. Motor neuron vulnerability could also be related to their unusual expression of inducible NO synthase (iNOS) in mitochondria.^274,275 Moreover, distal axonopathy and muscle disease may have roles in the pathogenesis in A53T mice.²⁶⁸ Prominent skeletal muscle denervation occurs in α-syn tg mice.^266,268 This work is intriguing because the original goal was to develop a tg mouse model of PD, but our result is a profound mouse model of ALS. Thus, the mutant α-syn A53T tg mouse is a new model to study mechanisms of motor neuron degeneration and could provide insight into the selective vulnerability of motor neurons in age-related disorders and the possible roles of α-syn in synaptic maintenance and diseases of long-axon neurons.²⁶⁸

E. Amyotrophic Lateral Sclerosis

ALS is a progressive and severely disabling neurological disease in humans characterized by initial muscle weakness, then muscle atrophy, spasticity, and eventual paralysis and death, typically 3–5 years after symptoms begin.²⁷⁶ The cause of the spasticity, paralysis, and death is progressive degeneration and elimination of upper motor neurons in cerebral cortex and lower motor neurons in brainstem and spinal cord (Fig. 6).^276,277 Degeneration and loss of spinal and neocortical interneurons also have been found in human ALS.^278,279 More than 5000 people in the United States are diagnosed with ALS each year (ALS Association, http://www.alsa.org), and, in parts of the United Kingdom, three people die every day from some form of motor neuron disease (http://www.mndassociation.org). Other than life support management, no effective treatments exist for ALS.²⁸⁰

Fig 6 — Motor neurons in spinal cord degenerate in ALS. (A) In normal control individuals, the anterior horns of the spinal cord contain many large, multipolar motor neurons (dark cells). (B) In ALS cases, the anterior horn is depleted of large neurons (dark cells) and remaining neurons are atrophic. These attritional chromatolytic motor neurons display a dark condensed nucleus as seen microscopically. Scale bar in A=76μm (same for B). (C, D, and E) Nissl staining shows that the degeneration of motor neurons in familial ALS is characterized by shrinkage and progressive condensation of the cytoplasm and nucleus. The motor neuron in (C) (arrow) appears normal. It has a large, multipolar cell body and a large nucleus containing a reticular network of chromatin and a large nucleolus. Scale bar=7 μm (same for D and E).The motor neuron in (D) (arrow) has undergone severe somatodentritic attrition. The motor neuron in (E) is at near end-stage degeneration (arrow). The cell has shrunken to ≈10% of its normal size and has become highly condensed. The cell in (E) is identified as a residual motor neuron based on the nucleus and nucleolus (seen as eccentrically placed darkly stained component to the lower left of cytoplasmic pale area) and residual large Nissl bodies. (F) Cell death assays (e.g., TUNEL) identify subsets of motor neurons in the process of DNA fragmentation. Nuclear DNA fragmentation (brown labeling) occurs in motor neurons as the nucleus condenses and the cell body shrinks. Motor neurons in the somatodendritic attrition stage accumulate DNA double strand breaks. Scale bar=7 μm. (G) In individuals with ALS, p53 accumulates in the nucleus (brown labeling) of motor neurons. Scale bar=5 μm. (H) Degenerating motor neurons in human ALS are immunopositive for cleaved caspase-3 (black-dark green labeling) in the somatodendritic attrition stage. Around the nucleus (pale circle), motor neurons accumulate discrete mitochondria (brown-orange labeling, detected with antibody to cytochrome c oxidase subunit I) exhibiting little light microscopic evidence for swelling. Scale bar=5μm.

It is still not understood why specific neuronal populations are selectively vulnerable in ALS, such as certain somatic motor neurons and interneurons.^276–279 The molecular pathogenesis of ALS is poorly understood, contributing to the lack of appropriate target identification and effective mechanism-based therapies to treat even the symptoms of this disease. As with other neurodegenerative diseases, both sporadic and familial forms of ALS occur. The majority of ALS is sporadic. Aging is a strong risk factor for ALS because the average age of onset is 55 years (ALS Association, www.alsa.org). Familial forms of ALS have autosomal-dominant or autosomal-recessive inheritance patterns and make up ≤10% of all ALS cases. ALS-linked mutations occur in the genes (Table III) encoding SOD1 (ALS1), Alsin (ALS2), senataxin (ALS4), fused in sarcoma (FUS, ALS6), vesicle associated membrane protein (VAMP/synaptobrevin)-associated protein B (VAPB, ALS8), p150 dynactin, and TAR-DNA binding protein (TADBP or TDP43).^281–284 Most recently, variations in the phosphoinositide phosphatase FIG4 gene have been found to cause ALS11.²⁸⁵ Several other genes are believed to be susceptibility factors for ALS (Table III).

TABLE III.

Mutant/Polymorphic Genes Linked to Familial ALS

Locus	Inheritance	Gene	Protein name/function
ALS1/21q22	Autosomal dominant (adult onset)	SOD1	Cu/Zn superoxide dismutase/dismutation of superoxide
ALS2/2q33.2	Autosomal recessive (juvenile onset primary lateral sclerosis)	Alsin	Alsin/guanine exchange factor for RAB5A and Rac1
ALS4/9q34	Autosomal dominant (adult onset)	SETX	Senataxin/helicase, RNA processing
ALS6/16q12	Autosomal recessive (adult onset)	FUS	Fused in sarcoma, component of heterogeneous nuclear ribonuclear protein complex; RNA/DNA-binding protein
ALS8/20q13.33	Autosomal dominant	VAPB	VAMP-associated protein B/part of SNARE complex
2q13	Autosomal dominant (adult onset, atypical ALS)	DCTN1	Dynactin p150^glued/axonal transport, link between dynein and microtubule network
ALS10/1p36.22	Autosomal dominant	TARDBP	TAR DNA-binding protein, DNA- and RNA-binding protein, regulates RNA splicing
ALS11/6q21	Autosomal recessive	FIG4	FIG4 homolog, SAC1 lipid phosphatase domain containing; regulates phosphotidylinositol turnover
14q11.1–q11.2	Susceptibility factor	ANG	Angiogenin; angiogenesis; stimulates production of rRNA
22q12.2	Susceptibility factor	NEFH	Neurofilament, heavy polypeptide; neurofilament subunit
12q12–q13	Susceptibility factor	PRPH	Peripherin; intermediate filament formation
5q13	Susceptibility factor	SMN1/SMN2	Survival motor neuron; RNA processing
7q36.6	Susceptibility factor?	DPP6	Dipeptidyl-peptidase 6; S9B serine protease, binds voltage-gated potassium channels

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F. Mitochondrial Dysfunction in Human ALS

Human ALS is associated with mitochondrial abnormalities. Structural abnormalities in mitochondria are seen by EM in skeletal muscle, liver, spinal motor neurons, and motor cortex of ALS patients.^286,287 A mutation in cytochrome c oxidase subunit I was found in a patient with a motor neuron disease phenotype.²⁸⁸ Another patient with motor neuron disease had a mutation in a mitochondrial tRNA gene.²⁸⁹ One type of mtDNA mutation, called the common mtDNA deletion (mtDNA4977), is found nonuniformly within different human brain areas. The highest levels are detected in the striatum and SN.^28,29 However, no significant accumulation of the 5-kb common deletion in mtDNA has been found by single-cell analysis of motor neurons from sporadic ALS cases compared to controls.²⁹⁰ This finding contrasts with the high levels of mtDNA deletions that accumulate in SNpc neurons in human PD.^291,292 Overall, there is a lack of strong direct evidence for mitochondrial involvement in human ALS, despite the existence of associational/correlative data from human, animal, or cell models.

Notwithstanding the lack of a clear seminal role for mitochondria in disease causation, intracellular Ca²⁺ abnormalities and excitotoxicity may link mitochondrial dysfunction and oxidative stress to ALS. Mitochondria regulate cytoplasmic Ca²⁺ levels.^1,3,293 EM on skeletal muscle biopsies of people with sporadic ALS shows changes indicative of elevated Ca²⁺ in motor neuron terminals, with some mitochondria showing an augmented Ca²⁺ signal.²⁹⁴ Excitotoxicity has long been implicated in the pathogenesis of ALS²⁹⁵ and is another possible mechanism of motor neuron damage in ALS.^216,276 While many drugs targeting excitotoxicity as a mechanism have failed in human ALS clinical trials, the anti-excitotoxic drug riluzole is currently approved by the Food and Drug Administration for ALS treatment.²⁸⁰ Many sporadic ALS patients have reduced levels of synaptosomal high-affinity glutamate uptake²⁹⁵ and astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2 or GLT1) in motor cortex and spinal cord.²⁹⁶ Reductions in levels of activity of EAAT2 in spinal cord could increase the extracellular concentrations of glutamate at synapses on motor neurons. Motor neurons might be particularly sensitive to glutamate excitotoxicity because they have a low proportion of GluR2- or under-edited AMPA subtype glutamate receptor on their surfaces, predisposing these cells to risk of excess Ca²⁺ entry and mitochondrial perturbations.^297,298 Cell culture studies show that excess glutamate receptor activation in neurons can cause increased intracellular Ca²⁺, mitochondrial ROS production, bioenergetic failure, and mitochondrial trafficking abnormalities.²⁹⁹ Ca²⁺-induced generation of ROS in brain mitochondria is mediated by mPT.³⁰⁰ Motor neurons are particularly affected by inhibition of mitochondrial metabolism, which can cause elevated cytosolic Ca²⁺ levels, excitability, and oxidative stress.³⁰¹

Markers of oxidative stress and ROS damage are elevated in postmortem human ALS tissues.³⁰² In sporadic and familial ALS, protein carbonyls are elevated in motor cortex.³⁰³ Tyrosine nitration is elevated in human ALS nervous tissues.^304–306 Studies of respiratory chain enzyme activities are discrepant. Experiments have shown increases in complex I–III activities (Fig. 1) in vulnerable and nonvulnerable brain regions in patients with familial ALS mutant SOD1,³⁰⁷ but experiments by others show decreased complex IV activity in spinal cord ventral horn³⁰⁸ and skeletal muscle³⁰⁹ of sporadic ALS cases. In sporadic ALS skeletal muscle, reductions in activity of respiratory chain complexes with subunits encoded by mtDNA are associated with reduced mtDNA content³⁰⁹ and decreased NOS levels.³¹⁰ Alterations in skeletal muscle mitochondria are progressive³¹¹ and could be intrinsic to skeletal muscle and not due merely to neurogenic atrophy, as commonly assumed.

G. Human ALS and Mitochondrial-Orchestrated PCD Involving p53

PCD appears to contribute to the selective degeneration of motor neurons in human ALS, albeit seemingly as a nonclassical form differing from apoptosis (Fig. 6).^312,313 Motor neurons appear to pass through sequential stages of chromatolysis, suggestive of initial axonal injury,²⁶⁹ somatodendritic attrition without extensive cytoplasmic vacuolation, and then nuclear DNA fragmentation, nuclear and chromatin condensation, and cell death (Fig. 6).³¹² Motor neurons in people who have died from sporadic ALS and familial ALS show the same type of degeneration.³¹² This cell death in human motor neurons is identified by genomic DNA fragmentation (determined by DNA agarose gel electrophoresis and in situ DNA nick-end labeling) and cell loss and is associated with accumulation of perikaryal mitochondria, cytochrome c, and cleaved caspase-3.^312–314 p53 protein also increases in vulnerable CNS regions in people with ALS, and it accumulates specifically in the nucleus of lower and upper motor neurons with nuclear DNA damage.^315–317 This p53 is active functionally because it is phosphorylated at Ser392 and has increased DNA-binding activity.^315,316 However, the morphology of this cell death is distinct from classical apoptosis, despite the nuclear condensation.^14,312,316 Nevertheless, Bax and Bak1 protein levels are increased in mitochondria-enriched fractions of selectively vulnerable motor regions (spinal cord anterior horn and motor cortex gray matter), but not in regions unaffected by the disease (somatosensory cortex gray matter).³¹² In marked contrast, Bcl-2 protein is depleted severely in mitochondria-enriched fractions of affected regions and is sequestered in the cytosol.³¹² Although these Western blot results lacked direct specificity for motor neuron events,³¹² subsequent immunohistochemistry (Fig. 6H)³¹³ and laser capture microdissection of motor neurons combined with mass spectroscopy-protein profiling have confirmed the presence of intact active caspase-3 in human ALS motor neurons.³¹⁴

Our studies^312–316 support the concept of an aberrant reemergence of a mitochondrial-directed PCD mechanism, involving p53 activation and redistributions of mitochondrial cell death proteins, participating in the pathogenesis of motor neuron degeneration in human ALS (Figs. 1 and 6). The morphological and biochemical changes seen in human ALS are modeled robustly and faithfully at structural and molecular levels in axonal injury/target deprivation (axotomy) models of motor neuron degeneration in adult rodents,^317,318 but not in the current most commonly used human mutant SOD1 tg mouse models.^274,313 However, we have created recently a new tg mouse expressing human mutant SOD1 only in skeletal muscle and have found a motor neuron disease phenotype with morphological and biochemical changes very similar that those seen in human ALS motor neurons.³¹⁹

H. Mitochondrial Pathobiology in Cell and Mouse Models of ALS

A common mutation in human SOD1 that is linked to familial ALS (Table III) is G93A.³²⁰ SOD1 is a metalloenzyme comprising 153 amino acids (≈16kDa) that binds one copper ion and one zinc ion per subunit and is active as a noncovalently linked homodimer.^5,321 SOD1 is responsible, through catalytic dismutation, for the detoxification and maintenance of intracellular O₂^•– concentration in the low femtomolar range (Fig. 1).^5,321 SOD1 is ubiquitous (intracellular SOD concentrations are typically ≈10–40μM) in most tissues, possibly with highest levels in neurons.³²²

Cell culture experiments reveal mitochondrial dysfunction in the presence of human mutant SOD1 (mSOD1).³²³ Expression of several mSOD1 variants increases mitochondrial O₂^•– levels and causes toxicity in rat primary embryonic motor neurons,³²⁴ human neuroblastoma cells,³²⁵ and mouse neuroblastoma-spinal cord (NSC)-34 cells, a hybrid cell line with some motor neuron-like characteristics produced by fusion of motor neuron-enriched embryonic mouse spinal cord cells with mouse neuroblastoma cells.³²⁶ These responses can be attenuated by overexpression of manganese SOD.³²⁵ ALS-mSOD1 variants, compared to human wild-type SOD1, associate more with mitochondria in NSC-34 cells and appear to form cross-linked oligomers that shift the mitochondrial GSH/GSSH ratio toward oxidation.³²³

Gurney et al. were the first to develop tg mice that express human mSOD1.^{313,320,327,328} In these mice, human mSOD1 is expressed ubiquitously, driven by its endogenous promoter in a tissue/cell nonselective pattern, against a background of normal wild-type mouse SOD1.³²⁷ Effects of this human mutant gene in mice are profound. Hemizygous tg mice expressing a high copy number of the G93A SOD1 mutant become completely paralyzed and die at ≈16–18 weeks of age.³²⁷ G93A-mSOD1 mice with reduced transgene copy number have a much slower disease progression and die at ≈8–9 months of age.^124,327

Spinal motor neurons and interneurons in mice expressing G93A^high-mSOD1 undergo prominent degeneration. About 80% of lumbar motor neurons are eliminated by end-stage disease.^274,329 Subsets of spinal interneurons degenerate before motor neurons in G93A^high-mSOD1 animals²⁷⁴ and some are the glycinergic Renshaw cells.³²⁹ Unlike the degeneration of motor neurons in human ALS,³¹² motor neurons in G93A^high-mSOD1 mice do not degenerate with a morphology resembling any form of apoptosis or hybrid apoptosis–necrosis.^{14,124,274,313,316} The motor neuron degeneration more closely resembles a prolonged necrotic-like cell death process^124,274 involving early occurring mitochondrial damage, cellular swelling, and dissolution.^{274,329–334} Biochemically, the death of motor neurons in G93A^high-mSOD1 is characterized by cell body and mitochondrial swelling, as well as the formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear DNA and mtDNA.²⁷⁴ The motor neuron death in G93A^high-mSOD1 mice is independent of activation of caspases-1 and -3 and also appears to be independent of caspase-8 and AIF activation.²⁷⁴ Indeed, caspase-dependent and p53-mediated apoptosis mechanisms might be blocked actively in G93A^high-mSOD1 mouse motor neurons, possibly by upregulation of IAPs and changes in the nuclear import of proteins.²⁷⁴ More work is needed on cell death and its mechanisms in G93A^low-mSOD1 mice because these mice could be more relevant physiologically and preclinically to the human disease, compared to the G93A^high-mSOD1 mouse.

Mitochondrial pathology has been implicated in the mechanisms of motor neuron degeneration in tg mSOD1 mouse models,^330–334 but until recently most evidence has been circumstantial. In different mSOD1 mouse models of ALS, mitochondria in spinal cord neurons exhibit structural pathology^{274,329–334} and some of the mitochondrial degeneration occurs very early in the course of the disease.^274,330 Mitochondrial microvacuolar damage in motor neurons emerges, as seen by EM, by 4 weeks of age in G93A^high mice.²⁷⁴ It has been argued that mitochondrial damage in G93A^high-mSOD1 mice is related to supranormal levels of SOD1 and might not be related causally to the disease process because tg mice expressing high levels of human wild-type SOD1 show some mitochondrial pathology.³³³ However, mitochondrial abnormalities in motor neurons have been found histologically in G93A^low-mSOD1 mice³³⁴ and in mice with only skeletal muscle expression of human SOD1.³¹⁹ Thus, mitochondria could be primary sites of human SOD1 toxicity in tg mice irrespective of transgene copy number, tissue expression, and expression level of human SOD1, but direct, unequivocal causal relationships have been lacking.

Mutated and wild-type forms of human SOD1 could contribute to the development of ALS. Human mSOD1 proteins appear to acquire a toxic property or function, rather than having diminished O₂^•– scavenging activity.^282,335,336 Wild-type SOD1 can gain toxic properties through loss of Zn³²⁴ and oxidative modification.^337,338 A gain in aberrant oxidative chemistry appears to contribute to the mechanisms of mitochondriopathy in G93A^high mice.^22,339 G93A-mSOD1 has enhanced free radical-generating capacity compared to wild-type enzyme³³⁶ and can catalyze protein oxidation by hydroxyl-like intermediates and carbonate radical.³⁴⁰ G93A^high mice have increased protein carbonyl formation in total spinal cord tissue extracts at presymptomatic disease stages.³⁴¹ Protein carbonyl formation in mitochondrial membrane-enriched fractions of spinal cord is a robust signature of incipient disease.³⁴¹ A mass spectroscopy study of G93A^high mice identified proteins in total spinal cord tissue extracts with greater than baseline carbonyl modification, including SOD1, translationally controlled tumor protein, and UCHL1.³⁴² Nitrated and aggregated cytochrome c oxidase subunit-I and α-syn accumulate in G93A^high mouse spinal cord.²⁷⁴ Nitrated MnSOD also accumulates in G93A^high mouse spinal cord.²⁷⁴

Toxic properties of mSOD1 might also be mediated through protein binding or aggregation. Endogenous mouse SOD1³⁴³ and human wild-type SOD1 and mSOD1³⁴⁴ associate with mitochondria. Human SOD1 mutants associate with spinal cord mitochondria in mSOD1 mice and can bind Bcl-2,³⁴⁵ thus potentially being decoys or dominant negative regulators of cell survival molecules (Fig. 1). It is not known whether this process occurs specifically in motor neurons. Binding of mSOD1 to mitochondria has been reported to be spinal cord-selective and age-dependent,³⁴⁶ but this work also lacks cellular resolution. A recent in vitro study has shown that endogenous SOD1 in the mitochondrial intermembrane space controls cytochrome c-catalyzed peroxidation and that G93A-mSOD1 mediates greater ROS production in the intermembrane space compared to wild-type SOD1.³⁴⁶ Human SOD1 mutants can also shift mitochondrial redox potential when expressed in cultured cells.³²³ Nevertheless, the direct links between the physicochemical changes in wild-type and mutant SOD1 and the mitochondrial functional and structural changes associated with ALS and motor neuron degeneration remain uncertain.

EM studies of motor neurons in G93A^high mice have shown that the OMM remains relatively intact to permit formation of mega-mitochondria.^{124,274,329,332} Moreover, early in the disease of these mice, mitochondria in dendrites in spinal cord ventral horn undergo extensive cristae and matrix remodeling, while few mitochondria in motor neuron cell bodies show major structural changes.¹²⁴ Thus, the disease might start distally in mitochondria of motor neuron processes.¹²⁴ Another interpretation of ultrastructural findings is that the mSOD1 causes mitochondrial degeneration by inducing OMM extension and leakage and intermembrane space expansion.³⁴⁷ Mechanisms for this damage could be related to mSOD1 gaining access to the mitochondrial intermembrane space.^343,344,347 This mitochondrial conformation seen by EM might favor the formation of the mPTP (Fig. 1). Indeed, we found evidence for increased contact sites between the OMM and the IMM in dendritic mitochondria in G93A^high mice.¹²⁴ Another feature of motor neurons in young G93A^high mice, before symptoms emerge, is the apparent fission of ultrastructurally normal mitochondria in cell bodies and fragmentation of abnormal mitochondria.¹²⁴ It is not clear whether the cristae and matrix remodeling and the apparent fragmentation and fission mitochondria are related or independent events, or whether these abnormalities interfere with mitochondrial trafficking. Nevertheless, morphological observations support the idea that mitochondria could be important for the pathobiology of mSOD1-induced toxicity of motor neurons in G93A^high mice.

We have hypothesized that mitochondrial trafficking perturbations occur in motor neurons of mSOD1.²⁷⁴ Some data support the novel idea that mitochondria might act as retrogradely transported couriers from distal regions (axon branches and dendrites) to the cell body of motor neurons in mSOD1 mice. G93A^high-mSOD1 mouse motor neurons accumulate mitochondria from the axon terminals and generate higher levels of O₂^•–, ^•NO, and ONOO^– than motor neurons in tg mice expressing human wild-type SOD1.²⁷⁴ This mitochondrial accumulation occurs at a time when motor neuron cell body volume is increasing, suggestive of ongoing abnormalities with ATP production or plasma membrane Na⁺,K⁺-ATPase.²⁷⁴ G93A-mSOD1 perturbs anterograde axonal transport of mitochondria in cultured primary embryonic motor neurons,³⁴⁸ making it possible that retrogradely transported mitochondria with toxic properties from the neuromuscular junction fail to be returned to distal processes.²⁷⁴ Mitochondria with enhanced toxic potential from distal axons and terminals could therefore have a “Trojan horse” role in triggering degeneration of motor neurons in ALS via retrograde transport from diseased skeletal muscle.

Motor neurons in G93A^high-mSOD1 mice also accumulate higher levels of intracellular Ca²⁺ than motor neurons in human wild-type SOD1 tg mice.²⁷⁴ The intracellular Ca²⁺ signal in motor neurons is very compartmental and mitochondrial-like in its appearance.^274,349 Abnormal elevations of intracellular Ca²⁺ in G93A^high-mSOD1 mouse motor neurons have been detected using a variety of Ca²⁺ detection methods.^350,351 Recent work on mouse neuromuscular junction preparations has shown that mitochondrial Ca²⁺ accumulation is accompanied by greater mitochondrial depolarization, specifically within motor neuron terminals of human mutant SOD1 tg mice.³⁵²

NO signaling mechanisms in mitochondria of ALS mice appear to be involved in pathogenesis. Motor neurons seem to be unique regarding NO production because they express constitutively low levels of iNOS.^274,275,349 G93A^high-mSOD1 mouse motor neurons accumulate nicotinamide adenine dinucleotide phosphate diaphorase and react with iNOS-specific antibodies.^274,275 iNOS also is upregulated aberrantly in human sporadic ALS motor neurons.³⁵³ iNos (Nos2) gene knockout²⁷⁴ and iNOS inhibition with 1400W²⁷⁵ extend significantly the lifespan of G93A^high-mSOD1 mice. Thus, mitochondrial oxidative stress, Ca²⁺ dysregulation, iNOS activation, protein nitration, and protein aggregation (not necessarily SOD1 aggregation) are all likely intrinsic, cell-autonomous mechanisms in the process of motor neuron degeneration caused by mSOD1 in mice.²⁷⁵ The mechanistic basis for the differences between human ALS and mSOD1 mice, regarding cell death phenotype,^{16,312,313,354} is not yet clear. The difference could be related to the extreme nonphysiological expression of toxic mSOD1, to fundamental differences in cell death mechanisms in human and mouse neurons,³⁵⁵ or to tissue inflammation that drives motor neurons in mSOD1 tg mice to necrotic-like death according to the cell death matrix.^7,354 Another contributing factor to this difference between human and mouse motor neurons is that mitochondria are functionally diverse and have species-specific activities and molecular compositions, including the makeup of the mPTP (Fig. 1).^7,355 These facts raise questions about the relevance of previous tg mSOD1 mouse to human ALS. Therefore, we recently have created a tg mouse with restricted expression of human SOD1 in skeletal muscle that develop ALS with a motor neuron degeneration phenotype similar to that seen in human ALS.³¹⁹

I. The MPTP Contributes to the Disease Mechanisms of ALS in Mice

Despite the implication of toxic effects of mSOD1 on mitochondria in mouse ALS, cause–effect relationships between abnormal functioning of mitochondria and initiation and progression of disease have been uncertain. These relationships need to be defined because this knowledge could lead to new mechanism-based treatments for ALS. One specific target of investigation for mitochondria in disease causality is the mPTP.

The mPTP was first implicated in mouse ALS pathogenesis using pharmacological approaches. Cyclosporine A treatment of G93A^high mice, delivered into the cerebral ventricle or systemically to mice on a multiple drug resistance type 1a/b background (to inactive the blood–brain barrier), improved outcome modestly.^356–358 These studies were confounded by the immunosuppressant actions of cyclosporine A through calcineurin inhibition. Pharmacological studies using CyPD inhibitors devoid of effects on calcineurin need to be done on ALS mice. Another study showed that treatment with cholest-4-en-3-one oxime (TRO19622), a drug that binds VDAC and the 18-kDa translocator protein (TSPO, or peripheral benzodiazepine receptor), improved motor performance, delayed disease onset, and extended survival of G93A^high mice.³⁵⁹ However, another study using a different TSPO ligand (Ro-4864) did not show positive effects with G93A^high mice.³⁶⁰

We identified CyPD and ANT as targets of nitration in ALS mice.¹²⁴ CyPD nitration is elevated in early to mid-symptomatic stages, but declines to baseline at end-stage disease.¹²⁴ ANT nitration is pertinent because it occurs in presymptomatic and symptomatic stages but not at end-stage disease or in tg mice expressing human wild-type SOD1.¹²⁴ The ANT is important in the context of age-related neurodegenerative disease because it undergoes carbonyl modification during aging, as seen in housefly flight muscle³⁶¹ and rat brain.³⁶²In vitro cell-free and cell experiments have shown that NO and ONOO^– can act directly on the ANT to induce mitochondrial permeabilization in a cyclosporine A-sensitive manner.³⁶³ Oxidative stress enhances the binding of CyPD to ANT.³⁶⁴ Some SOD1 mutants are unstable and lose copper,³⁶⁵ and interestingly, copper interactions or thiol modification of ANT can cause mPTP opening.^366,367 Together, these data and future work could reveal that oxidative and nitrative damage to proteins, some of which are core components of the mPTP, is targeted rather than stochastic and could impinge on the functioning of the mPTP.

We examined the role of CyPD in the process of motor neuron disease in ALS mice through gene ablation.¹²⁴ G93A^high-mSOD1 mice without CyPD showed markedly delayed disease onset and lived significantly longer than tg mice with CyPD. The effect of CyPD deletion was much more prominent in female mice than in male mice.¹²⁴ Female mice showed positive effects with only haplo-deletion of CyPD. Ppif gene ablation in tg mice with much lower levels of human mSOD1 expression and a slower disease progression (G93A^low-mSOD1 mice) also showed significantly delayed disease onset and lived significantly longer than tg mice with CyPD.¹²⁴ Thus, some form of mPTP pathobiology was occurring regardless of whether transgene expression of G93A is high or low. Nevertheless, most G93A-mSOD1 mice without CyPD eventually developed motor neuron disease and died. Other work on CypD null mice has shown that high concentrations of Ca²⁺ (2mM) can still lead to mPTP activation without CyPD and that cell deaths caused by Bid, Bax, DNA damage, and TNF-α still occur without CyPD.³⁶⁸ The effects of CyPD deficiency on motor neuron cell mechanisms thus need detailed examination, but the cell death phenotype might switch or convert to another form with the attenuation of mitochondrial swelling. A switch in cell death morphology and molecular mechanisms in motor neurons of mSOD1 mice without CyPD is an outcome consistent with the cell death matrix concept.^7,354

VII. Reflections

Mitochondria have diverse functions and properties and could be critically important for the development of AD, PD and ALS. Structural and biochemical data from studies of human autopsy CNS as well as cell and animal models of these neurodegenerative disorders suggest that mitochondrial dysfunction is a trigger or propagator of neurodegeneration. Novel mechanisms for mitochondriopathy and neurodegeneration could involve the mPTP (Fig. 1). There is precedence for this suggestion in mouse models of AD,¹⁹⁴ multiple sclerosis,³⁶⁹ stroke,³⁷⁰ and ALS.¹²⁴ The mPTP actively participates in the mechanisms of motor neuron death in ALS mice in a gender-dependent pattern.¹²⁴ Thus, mPTP activation is a possible triggering event for motor neuron degeneration, and motor neuron selective vulnerability in ALS could be related to the amount, composition, and trafficking of mitochondria in these cells. The disappointing negative results of the recent minocycline clinical trial in ALS³⁷¹ should not be viewed as an outcome contradictory to the mPTP hypothesis in neurodegeneration, but instead as an example of the difficulty in adequately interpreting the in vivo effects of a multifunctional drug in a disease process and the importance of identifying and selecting appropriate dosing regimens. Basic biological considerations also may be relevant. For example, cell death and inflammatory mechanisms in human and mice are different,³¹³ so the effects of minocycline could differ. Further study of mitochondria and the mPTP in human and rodent neurons, glial cells, and skeletal myocytes may define new mechanisms of disease and lead to the identification of molecular mechanism-based therapies for treating PD and ALS.

Acknowledgments

This chapter is dedicated to Albert Lehninger for his seminal work on mitochondria done while Chair of the Department of Biological Chemistry at Johns Hopkins University School of Medicine. The author thanks all of the individuals in his lab for their hard work, particularly Yan Pan and Ann Price for data generated on human PD and ALS autopsy brain and spinal cord, the A53T α-syn tg mouse, and the G93A-mSOD1 tg mouse. This work was supported by grants from the U.S. Public Health Service, NIH-NINDS (NS034100, NS065895, NS052098) and NIH-NIA (AG016282).

Abbreviations

Aβ: amyloid β-protein
AD: Alzheimer's disease
AIF: apoptosis-inducing factor
ALS: amyotrophic lateral sclerosis
ANT: adenine nucleotide translocator
Apaf: apoptotic protease activating factor
APE: apurinic/apyrimidinic endonuclease (aka, HAP1)
ApoE: apolipoprotein E
APP: amyloid precursor protein
Bax: Bcl-2-associated X protein
Bak1: Bcl-2-antagonist/killer 1
Bcl: B-cell lymphoma
BER: DNA base excision repair
CNS: central nervous system
Cu/ZnSOD: copper/zinc superoxide dismutase (also SOD1)
CyPD: cyclophilin D
Caspase: cysteinyl aspartate-specific proteinase
DISC: death-inducing signaling complex
EM: electron microscopy
ER: endoplasmic reticulum
GPe: globus pallidus external
GPi: globus pallidus internal
HtrA2: high-temperature requirement protein A2
IAP: inhibitor of apoptosis protein
IMM: inner mitochondrial membrane
KA: kainic acid
LB: Lewy body
LRRK2: leucine-rich repeat kinase 2
Mfn: mitofusin
MnSOD: manganese SOD (also SOD2)
mPT: mitochondrial permeability transition
mPTP: mitochondrial permeability transition pore
mSOD1: mutant SOD1
mtDNA: mitochondrial DNA
NAIP: neuronal apoptosis inhibitory protein
NFT: neurofibrillary tangle
NMDA: N-methyl-d-aspartate
NO: nitric oxide
NOS: nitric oxide synthase
NSC-34: neuroblastoma-spinal cord-34
O₂^•–: superoxide radical
OGG1: 8-oxoguanine DNA glycosylase-1
OMM: outer mitochondrial membrane
ONOO^–: peroxynitrite
OPA: optic atrophy type 1
PCD: programmed cell death
PEO: progressive external ophthalamoplegia
PD: Parkinson's disease
PINK1: phosphatase and tensin homolog-induced putative kinase-1
POLG: DNA polymerase γ
ROS: reactive oxygen species
Smac: second mitochondria-derived activator of caspases
SNpc: substantia nigra pars compacta
α-Syn: α-synuclein
Tg: transgenic
TIMM: translocase of inner mitochondrial membrane
TOMM: translocase of outer mitochondrial membrane
TSPO: translocator protein 18kDa (peripheral benzodiazepine receptor)
TNF: tumor necrosis factor
TUNEL: terminal transferase-mediated biotin-dUTP nick-end labeling
UCHL1: ubiquitin carboxy-terminal hydrolyase-L1
VDAC: voltage-dependent anion channel

References

1.Zorov DB, Isave NK, Plotnikov EY, Zorova LD, Stelmashook EV, Vasileva AK, et al. The mitochondrion as Janus Bifrons. Biochemistry (Mosc) 2007;72:1115–26. doi: 10.1134/s0006297907100094. [DOI] [PubMed] [Google Scholar]
2.Halliwell B. Role of free radicals in the neurodegenerative diseases. Drugs Aging. 2001;18:685–716. doi: 10.2165/00002512-200118090-00004. [DOI] [PubMed] [Google Scholar]
3.Nicholls DG. Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int J Biochem Cell Biol. 2002;34:1372–81. doi: 10.1016/s1357-2725(02)00077-8. [DOI] [PubMed] [Google Scholar]
4.Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn of evolutionary medicine. Annu Rev Genet. 2002;39:359–407. doi: 10.1146/annurev.genet.39.110304.095751. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97–112. doi: 10.1146/annurev.bi.64.070195.000525. [DOI] [PubMed] [Google Scholar]
6.Mungrue IN, Bredt DS, Stewart DJ, Husain M. From molecules to mammals: what's NOS got to do with it? Acta Physiol Scand. 2003;179:123–35. doi: 10.1046/j.1365-201X.2003.01182.x. [DOI] [PubMed] [Google Scholar]
7.Martin LJ. Mitochondrial and cell death mechanisms in neurodegenerative disease. Pharmaceuticals. 2010;3:839–915. doi: 10.3390/ph3040839. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Delettre C, Lenaers G, Pelloquin L, Belenguer P, Hamel CP. OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol Genet Metab. 2002;75:97–107. doi: 10.1006/mgme.2001.3278. [DOI] [PubMed] [Google Scholar]
9.Chen H, Chan DC. Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet. 2005;14:R283–9. doi: 10.1093/hmg/ddi270. [DOI] [PubMed] [Google Scholar]
10.Brown MD, Voljavec AS, Lott MT, MacDolald I, Wallace DC. Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB J. 1992;6:2791–9. doi: 10.1096/fasebj.6.10.1634041. [DOI] [PubMed] [Google Scholar]
11.Wong L-JC, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, et al. Molecular and clinical genetics of mitochondrial disease due to POLG mutations. Hum Mutat. 2008;29:E150–72. doi: 10.1002/humu.20824. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Goffart S, Cooper HM, Tyynismaa H, Wanrooij S, Suomalainen A, Spelbrink JN. Twinkle mutations associated with autosomal dominant progressive external opthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet. 2009;18:328–40. doi: 10.1093/hmg/ddn359. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Komaki H, Fukazawa T, Houzen H, Yoshida K, Nonaka I, Goto Y. A novel D104G mutation in the adenine nucleotide translocator 1 gene in autosomal dominant external opthalmoplegia patients with mitochondrial DNA with multiple deletions. Ann Neurol. 2002;51:645–8. doi: 10.1002/ana.10172. [DOI] [PubMed] [Google Scholar]
14.Martin LJ, Al-Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera-Cailliau C. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull. 1998;46:281–309. doi: 10.1016/s0361-9230(98)00024-0. [DOI] [PubMed] [Google Scholar]
15.Northington FJ, Graham EM, Martin LJ. Apoptosis in perinatal hypoxic-ischemic brain injury: how important is it and should it be inhibited? Brain Res Rev. 2005;50:244–57. doi: 10.1016/j.brainresrev.2005.07.003. [DOI] [PubMed] [Google Scholar]
16.Martin LJ. The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis. Biochim Biophys Acta. 2010;1802:186–97. doi: 10.1016/j.bbadis.2009.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters JJ. Cyclophilin D as a drug target. Curr Med Chem. 2003;10:1485–506. doi: 10.2174/0929867033457160. [DOI] [PubMed] [Google Scholar]
18.Crompton M. Mitochondria and aging: a role for the permeability transition? Aging Cell. 2004;3:3–6. doi: 10.1046/j.1474-9728.2003.00073.x. [DOI] [PubMed] [Google Scholar]
19.Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol. 2009;46:821–31. doi: 10.1016/j.yjmcc.2009.02.021. [DOI] [PubMed] [Google Scholar]
20.Bernardi P, Krauskopf A, Basso E, Petronilli V, Blalchy-Dyson E, Di Lisa F, et al. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J. 2006;273:2077–99. doi: 10.1111/j.1742-4658.2006.05213.x. [DOI] [PubMed] [Google Scholar]
21.Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, et al. Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005;19:2040–1. doi: 10.1096/fj.05-3735fje. [DOI] [PubMed] [Google Scholar]
22.Beckman JS, Carson M, Smith CD, Koppenol WH. ALS, SOD and peroxynitrite. Nature. 1993;364:548. doi: 10.1038/364584a0. [DOI] [PubMed] [Google Scholar]
23.Martin LJ, Liu Z. DNA damage profiling in motor neurons: a single-cell analysis by comet assay. Neurochem Res. 2002;27:1089–100. doi: 10.1023/a:1020961006216. [DOI] [PubMed] [Google Scholar]
24.Giulini C. Characterization and function of mitochondrial nitric-oxide synthase. Free Radic Biol Med. 2003;34:397–408. doi: 10.1016/s0891-5849(02)01298-4. [DOI] [PubMed] [Google Scholar]
25.Brown GC, Borutaite V. Nitric oxide, cytochrome c, and mitochondria. Biochem Soc Symp. 1999;66:17–25. doi: 10.1042/bss0660017. [DOI] [PubMed] [Google Scholar]
26.Choi DW. Cellular defences destroyed. Nature. 2005;433:696–8. doi: 10.1038/433696a. [DOI] [PubMed] [Google Scholar]
27.Brown MR, Sullivan PG, Geddes JW. Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria. J Biol Chem. 2006;281:11658–68. doi: 10.1074/jbc.M510303200. [DOI] [PubMed] [Google Scholar]
28.Soong NW, Hinton DR, Cortopassi G, Arnheim N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet. 1992;2:318–23. doi: 10.1038/ng1292-318. [DOI] [PubMed] [Google Scholar]
29.Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet. 1992;2:324–9. doi: 10.1038/ng1292-324. [DOI] [PubMed] [Google Scholar]
30.Driggers WJ, LeDoux SP, Wilson GL. Repair of oxidative damage within the mitochondrial DNA or RINr 38 cells. J Biol Chem. 1993;268:22042–5. [PubMed] [Google Scholar]
31.Larsen NB, Rasmussen M, Rasmussen LJ. Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion. 2005;5:89–108. doi: 10.1016/j.mito.2005.02.002. [DOI] [PubMed] [Google Scholar]
32.Szczesny B, Hazra TK, Papaconstantinou J, Mitra S, Boldogh I. Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci USA. 2003;100:10670–5. doi: 10.1073/pnas.1932854100. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Popp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics. 1996;36:449–58. doi: 10.1006/geno.1996.0490. [DOI] [PubMed] [Google Scholar]
34.Gunawardena S, Goldstein LSB. Cargo-carrying motor vehicles on the neuronal highway: transport pathways and neurodegenerative disease. J Neurobiol. 2003;58:258–71. doi: 10.1002/neu.10319. [DOI] [PubMed] [Google Scholar]
35.Chada SR, Hollenbeck PJ. Mitochondrial movement and positioning in axons: the role of growth factor signaling. J Exp Biol. 2003;206:1985–92. doi: 10.1242/jeb.00263. [DOI] [PubMed] [Google Scholar]
36.Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, Harada A, et al. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell. 1998;93:1147–58. doi: 10.1016/s0092-8674(00)81459-2. [DOI] [PubMed] [Google Scholar]
37.Ligon LA, Steward O. Role of microtubules and actin filaments in the movement of mitochondria in the axons and dendrites of cultured hippocampal neurons. J Comp Neurol. 2000;427:351–61. doi: 10.1002/1096-9861(20001120)427:3<351::aid-cne3>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
38.Pintoul GL, Filiano AJ, Brocard JB, Kress GJ, Reynolds IJ. Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J Neurosci. 2003;23:7881–8. doi: 10.1523/JNEUROSCI.23-21-07881.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Reynolds IJ, Malaiyandi LM, Coash M, Rintoul GL. Mitochondrial trafficking in neurons: a key variable in neurodegeneration? J Bioeng Biomembr. 2004;36:283–6. doi: 10.1023/B:JOBB.0000041754.78313.c2. [DOI] [PubMed] [Google Scholar]
40.Miller KE, Sheetz MP. Axonal mitochondrial transport and potential are correlated. J Cell Sci. 2004;117:2791–804. doi: 10.1242/jcs.01130. [DOI] [PubMed] [Google Scholar]
41.Tatebayashi Y, Haque N, Tung YC, Iqbal K, Grundke-Iqbal I. Role of tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport. J Cell Sci. 2004;117:1653–63. doi: 10.1242/jcs.01018. [DOI] [PubMed] [Google Scholar]
42.Martin LJ. Neuronal cell death in nervous system development, disease, and injury. Int J Mol Med. 2001;7:455–78. [PubMed] [Google Scholar]
43.Lockshin RA, Zakeri Z. Caspase-independent cell deaths. Curr Opin Cell Biol. 2002;14:727–33. doi: 10.1016/s0955-0674(02)00383-6. [DOI] [PubMed] [Google Scholar]
44.Gilbert S. Developmental biology. Sinauer Associates; Sunderland: 2006. [Google Scholar]
45.Ameisen JC. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ. 2002;9:367–93. doi: 10.1038/sj.cdd.4400950. [DOI] [PubMed] [Google Scholar]
46.Metzstein MM, Stanfield GM, Horvitz HR. Genetics of programmed cell death in C. elegans: past, present and future. Trends Genet. 1998;14:410–6. doi: 10.1016/s0168-9525(98)01573-x. [DOI] [PubMed] [Google Scholar]
47.Youle RJ, Strasser A. The Bcl-2 protein family: opposing activities that mediate cell death. Nat Rev. 2008;9:47–59. doi: 10.1038/nrm2308. [DOI] [PubMed] [Google Scholar]
48.Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci. 1997;20:245–67. doi: 10.1146/annurev.neuro.20.1.245. [DOI] [PubMed] [Google Scholar]
49.Cory S, Adams JM. The bcl-2 family: regulators of the cellular life-or-death switch. Nat Rev. 2002;2:647–56. doi: 10.1038/nrc883. [DOI] [PubMed] [Google Scholar]
50.Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem. 1999;274:20049–52. doi: 10.1074/jbc.274.29.20049. [DOI] [PubMed] [Google Scholar]
51.Nagata S. Fas ligand-induced apoptosis. Annu Rev Genet. 1999;33:29–55. doi: 10.1146/annurev.genet.33.1.29. [DOI] [PubMed] [Google Scholar]
52.Levrero M, De Laurenzi V, Costanzo A, Sabatini S, Gong J, Wang JYJ, et al. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci. 2000;113:1661–70. doi: 10.1242/jcs.113.10.1661. [DOI] [PubMed] [Google Scholar]
53.Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91:479–89. doi: 10.1016/s0092-8674(00)80434-1. [DOI] [PubMed] [Google Scholar]
54.Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–57. doi: 10.1016/s0092-8674(00)80085-9. [DOI] [PubMed] [Google Scholar]
55.Klein JA, Longo-Guess CM, Rossmann MP, Seburn RE, Hurd RE, Frankel WN, et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002;419:367–74. doi: 10.1038/nature01034. [DOI] [PubMed] [Google Scholar]
56.Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilentei L, et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem. 2002;277:432–4538. doi: 10.1074/jbc.M109721200. [DOI] [PubMed] [Google Scholar]
57.Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature. 1996;379:349–53. doi: 10.1038/379349a0. [DOI] [PubMed] [Google Scholar]
58.Scorrano L, Oakes SA, Opferman TJ, Cheng EH, Sorcinelli MD, Pozzan T, et al. Bax and Bak regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science. 2003;300:135–9. doi: 10.1126/science.1081208. [DOI] [PubMed] [Google Scholar]
59.Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature. 1999;381:335–41. doi: 10.1038/381335a0. [DOI] [PubMed] [Google Scholar]
60.Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, et al. Inhibition of bax channel-forming activity by bcl-2. Science. 1997;277:370–2. doi: 10.1126/science.277.5324.370. [DOI] [PubMed] [Google Scholar]
61.Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2:183–92. doi: 10.1016/s1535-6108(02)00127-7. [DOI] [PubMed] [Google Scholar]
62.Wei MC, Zong W-X, Cheng EH-Y, Lindsten T, Panoutsakopoulou V, Ross AJ, et al. Proapoptotic Bax and Bak: a requisite gateway to mitochondrial dysfunction and death. Science. 2001;292:727–30. doi: 10.1126/science.1059108. [DOI] [PMC free article] [PubMed] [Google Scholar]
63.Shimizu S, Ide T, Yanagida T, Tsujimoto Y. Electrophysiological study of a novel large pore formed by Bax and the voltage-dependent anion channel that is permeable to cytochrome c. J Biol Chem. 2000;275:12321–5. doi: 10.1074/jbc.275.16.12321. [DOI] [PubMed] [Google Scholar]
64.Chowdhury I, Tharakan B, Bhat GH. Caspases—an update. Comp Biochem Physiol. 2008;51:10–27. doi: 10.1016/j.cbpb.2008.05.010. [DOI] [PubMed] [Google Scholar]
65.Mancini M, Nicholson DW, Roy S, Thornberry NA, Peterson EP, Casciola-Rosen LA, et al. The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. J Cell Biol. 1998;140:1485–95. doi: 10.1083/jcb.140.6.1485. [DOI] [PMC free article] [PubMed] [Google Scholar]
66.Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraus QL, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA. 1999;96:5752–7. doi: 10.1073/pnas.96.10.5752. [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997;89:175–84. doi: 10.1016/s0092-8674(00)80197-x. [DOI] [PubMed] [Google Scholar]
68.Li H, Zhu H, Xu C-J, Yuan J. Cleavage of Bid by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94:491–501. doi: 10.1016/s0092-8674(00)81590-1. [DOI] [PubMed] [Google Scholar]
69.Robertson JD, Enoksson M, Suomela M, Zhivotovsky B, Orrenius S. Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis. J Biol Chem. 2002;277:29803–9. doi: 10.1074/jbc.M204185200. [DOI] [PubMed] [Google Scholar]
70.LaCasse EC, Baird S, Korneluk RG, MacKenzie AE. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 1998;17:3247–59. doi: 10.1038/sj.onc.1202569. [DOI] [PubMed] [Google Scholar]
71.Holcik M. The IAP proteins. Trends Genet. 2002;18:537–8. doi: 10.1016/s0168-9525(02)02743-9. [DOI] [PubMed] [Google Scholar]
72.Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 1998;17:2215–23. doi: 10.1093/emboj/17.8.2215. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Hao Y, Sekine K, Kawabata A, Nakamura H, Ishioka T, Ohata H, et al. Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function. Nat Cell Biol. 2004;6:849–60. doi: 10.1038/ncb1159. [DOI] [PubMed] [Google Scholar]
74.Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42. doi: 10.1016/s0092-8674(00)00008-8. [DOI] [PubMed] [Google Scholar]
75.Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000;102:43–53. doi: 10.1016/s0092-8674(00)00009-x. [DOI] [PubMed] [Google Scholar]
76.Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 2001;8:613–21. doi: 10.1016/s1097-2765(01)00341-0. [DOI] [PubMed] [Google Scholar]
77.Bogaerts V, Nuytemans K, Reumers J, Pals R, Engelborghs S, Pickut B, et al. Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson's disease. Hum Mutat. 2008;29:832–40. doi: 10.1002/humu.20713. [DOI] [PubMed] [Google Scholar]
78.Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397:441–6. doi: 10.1038/17135. [DOI] [PubMed] [Google Scholar]
79.Mate MJ, Ortiz-Lombardia M, Boitel B, Haouz A, Tello D, Susin SA, et al. The crystal structure of the mouse apoptosis-inducing factor AIF. Nat Struct Biol. 2002;9:442–6. doi: 10.1038/nsb793. [DOI] [PubMed] [Google Scholar]
80.Trump BF, Berezesky IK. The role of altered [Ca2+]i regulation in apoptosis, oncosis, and necrosis. Biochim Biophys Acta. 1996;1313:173–8. doi: 10.1016/0167-4889(96)00086-9. [DOI] [PubMed] [Google Scholar]
81.Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995;146:3–15. [PMC free article] [PubMed] [Google Scholar]
82.Trump BJ, Goldblatt PJ, Stowell RE. Studies on necrosis of mouse liver in vitro. Ultrastructural alterations in the mitochondria of hepatic parenchymal cells. Lab Invest. 1964;14:343–71. [PubMed] [Google Scholar]
83.Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell culture. Proc Natl Acad Sci USA. 1995;92:7162–6. doi: 10.1073/pnas.92.16.7162. [DOI] [PMC free article] [PubMed] [Google Scholar]
84.Leist M, Single B, Castoldi AF, Kuhnles S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med. 1997;185:1481–6. doi: 10.1084/jem.185.8.1481. [DOI] [PMC free article] [PubMed] [Google Scholar]
85.Golden WC, Brambrink AM, Traystman RJ, Martin LJ. Failure to sustain recovery of Na, K ATPase function is a possible mechanism for striatal neurodegeneration in hypoxic-ischemic newborn piglets. Mol Brain Res. 2001;88:94–102. doi: 10.1016/s0169-328x(01)00032-8. [DOI] [PubMed] [Google Scholar]
86.Castro J, Ruminot I, Porras OH, Flores CM, Hermosilla T, Verdugo E, et al. ATP steal between cation pumps: a mechanism linking Na+ influx to the onset or necrotic Ca2+ overload. Cell Death Differ. 2006;13:1675–85. doi: 10.1038/sj.cdd.4401852. [DOI] [PubMed] [Google Scholar]
87.Proskuryakov SY, Konoplyannikov AG, Gabai VL. Necrosis: a specific form of programmed cell death. Exp Cell Res. 2003;283:1–16. doi: 10.1016/s0014-4827(02)00027-7. [DOI] [PubMed] [Google Scholar]
88.Kim Y-S, Morgan MJ, Choksi S, Lu Z-G. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell. 2007;26:675–87. doi: 10.1016/j.molcel.2007.04.021. [DOI] [PubMed] [Google Scholar]
89.Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008;135:1311–23. doi: 10.1016/j.cell.2008.10.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
90.Baines CP, Kaiser RA, Purcell NH, Blair HS, Osinska H, Hambleton MA, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005;434:658–62. doi: 10.1038/nature03434. [DOI] [PubMed] [Google Scholar]
91.Ha HC, Snyder SH. Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis. 2000;7:225–39. doi: 10.1006/nbdi.2000.0324. [DOI] [PubMed] [Google Scholar]
92.Zoratti M, Szabo I. The mitochondrial permeability transition. Biochem Biophys Acta. 1995;1241:139–76. doi: 10.1016/0304-4157(95)00003-a. [DOI] [PubMed] [Google Scholar]
93.Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999;341:233–49. [PMC free article] [PubMed] [Google Scholar]
94.van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P. Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun. 2003;304:487–97. doi: 10.1016/s0006-291x(03)00621-1. [DOI] [PubMed] [Google Scholar]
95.Leung AWC, Halestrap AP. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta. 2008;1777:946–52. doi: 10.1016/j.bbabio.2008.03.009. [DOI] [PubMed] [Google Scholar]
96.Shoshan-Barmatz V, Israelson A, Brdiczka D, Sheu SS. The voltage-dependent anion channel (VDAC): function in intracellular signaling, cell life and cell death. Curr Pharm Des. 2006;12:2249–70. doi: 10.2174/138161206777585111. [DOI] [PubMed] [Google Scholar]
97.Rostovtseva TK, Tan W, Colombini M. On the role of VDAC in apoptosis: fact and fiction. J Bioenerg Biomembr. 2005;37:129–42. doi: 10.1007/s10863-005-6566-8. [DOI] [PubMed] [Google Scholar]
98.Tan W, Colombini M. VDAC closure increases calcium ion flux. Biochim Biophys Acta. 2007;1768:2510–5. doi: 10.1016/j.bbamem.2007.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
99.Tikunov A, Johnson CB, Pediaditakis P, Markevich N, MacDonald JM, Lemasters JJ, et al. Closure of VDAC causes oxidative stress and accelerates the Ca2+-induced mitochondrial permeability transition in rat liver mitochondria. Arch Biochem Biophys. 2010;495:174–81. doi: 10.1016/j.abb.2010.01.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
100.Granville DJ, Gottlieb RA. The mitochondrial voltage-dependent anion channel (VDAC) as a therapeutic target for initiating cell death. Curr Med Chem. 2003;10:1527–33. doi: 10.2174/0929867033457214. [DOI] [PubMed] [Google Scholar]
101.Huizing M, Ruitenbeek W, van den Heuvel LP, Dolce V, Iacobazzi V, Smeitink JAM, et al. Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders. J Bioenerg Biomembr. 1998;30:277–84. doi: 10.1023/a:1020501021222. [DOI] [PubMed] [Google Scholar]
102.Wu S, Sampson MJ, Decker WK, Craigen WJ. Each mammalian mitochondrial outer membrane porin protein is dispensable: effects on cellular respiration. Biochem Biophys Acta. 1999;1452:68–78. doi: 10.1016/s0167-4889(99)00120-2. [DOI] [PubMed] [Google Scholar]
103.Anflous K, Armstrong DD, Craigen WJ. Altered sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice. J Biol Chem. 2001;276:1954–60. doi: 10.1074/jbc.M006587200. [DOI] [PubMed] [Google Scholar]
104.Sampson MJ, Decker WK, Beaudet AL, Ruitenbeek W, Armstrong D, Hicks MJ, et al. Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J Biol Chem. 2001;276:39206–12. doi: 10.1074/jbc.M104724200. [DOI] [PubMed] [Google Scholar]
105.Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsemeyer SJ. VDAC2 inhibits Bak activation and mitochondrial apoptosis. Science. 2003;301:513–7. doi: 10.1126/science.1083995. [DOI] [PubMed] [Google Scholar]
106.Chandra D, Choy G, Daniel PT, Tang DG. Bax-dependent regulation of Bak by voltage-dependent anion channel 2. J Biol Chem. 2005;280:19051–61. doi: 10.1074/jbc.M501391200. [DOI] [PubMed] [Google Scholar]
107.Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol. 2007;9:550–5. doi: 10.1038/ncb1575. [DOI] [PMC free article] [PubMed] [Google Scholar]
108.Karachitos A, Galganska H, Wojtkowska M, Budzinska M, Stobienia O, Bartosz G, et al. Cu, Zn-superoxide dismutase is necessary for proper function of VDAC in Saccharomyces cerevisiae cells. FEBS Lett. 2009;583:449–55. doi: 10.1016/j.febslet.2008.12.045. [DOI] [PubMed] [Google Scholar]
109.Halestrap AP, Brenner C. The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death. Curr Med Chem. 2003;10:1507–25. doi: 10.2174/0929867033457278. [DOI] [PubMed] [Google Scholar]
110.Graham BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR, Wallace DC. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat Genet. 1997;16:226–34. doi: 10.1038/ng0797-226. [DOI] [PubMed] [Google Scholar]
111.Stepien G, Torroni A, Chung AB, Hodge JA, Wallace DC. Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during muscle cell differentiation. J Biol Chem. 1992;267:14592–7. [PubMed] [Google Scholar]
112.Vyssokikh MY, Katz A, Rueck A, Wuensch C, Dorner A, Zorov DB, et al. Adenine nucleotide translocator isoforms 1 and 2 are differently distributed in the mitochondrial inner membrane and have distinct affinities to cyclophilin D. Biochem J. 2001;358:349–58. doi: 10.1042/0264-6021:3580349. [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Kikoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature. 2004;427:461–5. doi: 10.1038/nature02229. [DOI] [PMC free article] [PubMed] [Google Scholar]
114.Machida K, Hayashi Y, Osada H. A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome c release through a mitochondrial permeability transition-independent mechanisms. J Biol Chem. 2002;277:31243–8. doi: 10.1074/jbc.M204564200. [DOI] [PubMed] [Google Scholar]
115.Woodfield K, Rück A, Brdiczka D, Halestrap AP. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J. 1998;336:287–90. doi: 10.1042/bj3360287. [DOI] [PMC free article] [PubMed] [Google Scholar]
116.Johnson N, Khan A, Virji S, Ward JM, Crompton M. Import and processing of heart mitochondrial cyclophilin D. Eur J Biochem. 1999;263:353–9. doi: 10.1046/j.1432-1327.1999.00490.x. [DOI] [PubMed] [Google Scholar]
117.McEnery MW, Dawson TM, Verma A, Gurley D, Colombini M, Snyder SH. Mitochondrial voltage-dependent anion channel. J Biol Chem. 1993;268:23289–96. [PubMed] [Google Scholar]
118.Shoshan-Barmatz V, Zalk R, Gincel D, Vardi N. Subcellular localization of VDAC in mitochondria and ER in the cerebellum. Biochem Biophys Acta. 2004;1657:105–14. doi: 10.1016/j.bbabio.2004.02.009. [DOI] [PubMed] [Google Scholar]
119.Akanda N, Tofight R, Brask J, Tamm C, Elinder F, Ceccatelli S. Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells. Cell Cycle. 2008;7:3225–34. doi: 10.4161/cc.7.20.6831. [DOI] [PubMed] [Google Scholar]
120.Yu WH, Wolfgang W, Forte M. Subcellular localization of human voltage-dependent anion channel isoforms. J Biol Chem. 1995;270:13998–4006. doi: 10.1074/jbc.270.23.13998. [DOI] [PubMed] [Google Scholar]
121.Buck CR, Jurynec MJ, Upta DE, Law AKT, Bilger J, Wallace DC, et al. Increased adenine nucleotide translocator 1 in reactive astrocytes facilitates glutamate transport. Exp Neurol. 2003;181:149–58. doi: 10.1016/s0014-4886(03)00043-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
122.Hazelton JL, Petrasheuskaya M, Fiskum G, Kristian T. Cyclophilin D is expressed predominantly in mitochondria of γ-aminobutyric acidergic interneurons. J Neurosci Res. 2009;87:1250–9. doi: 10.1002/jnr.21921. [DOI] [PMC free article] [PubMed] [Google Scholar]
123.Naga KK, Sullivan PG, Geddes JW. High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition. J Neurosci. 2007;27:7469–75. doi: 10.1523/JNEUROSCI.0646-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
124.Martin LJ, Gertz B, Pan Y, Price AC, Molkentin JD, Chang Q. The mitochondrial permeability transition pore in motor neurons: involvement in the pathobiology of ALS mice. Exp Neurol. 2009;218:333–46. doi: 10.1016/j.expneurol.2009.02.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Bose S, Freedman RB. Peptidyl prolyl cis-trans-isomerase activity associated with the lumen of the endoplasmic reticulum. Biochem J. 1994;300:865–70. doi: 10.1042/bj3000865. [DOI] [PMC free article] [PubMed] [Google Scholar]
126.Sullivan PG, Rabchevsky AG, Keller JN, Lovell M, Sodhi A, Hart RP, et al. Intrinsic differences in brain and spinal cord mitochondria: implications for therapeutic interventions. J Comp Neurol. 2004;474:524–34. doi: 10.1002/cne.20130. [DOI] [PubMed] [Google Scholar]
127.Morota S, Hansson MJ, Ishii N, Kudo Y, Elmer E, Uchino H. Spinal cord mitochondria display lower calcium retention capacity compared with brain mitochondria without inherent differences in sensitivity to cyclophilin D inhibition. J Neurochem. 2007;103:2066–76. doi: 10.1111/j.1471-4159.2007.04912.x. [DOI] [PubMed] [Google Scholar]
128.Collins TJ, Bootman MD. Mitochondria are morphologically heterogeneous within cells. J Exp Biol. 2003;206:1993–2000. doi: 10.1242/jeb.00244. [DOI] [PubMed] [Google Scholar]
129.Jensen RE. Control of mitochondrial shape. Curr Opin Cell Biol. 2005;17:384–8. doi: 10.1016/j.ceb.2005.06.011. [DOI] [PubMed] [Google Scholar]
130.Hamberger A, Blomstrand C, Lehninger AL. Comparative studies of mitochondria isolated from neuron-enriched and glia-enriched fractions of rabbit and beef brain. J Cell Biol. 1970;45:221–34. doi: 10.1083/jcb.45.2.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
131.Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290:1717–21. doi: 10.1126/science.290.5497.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Tolkovsky AM, Xue L, Fletcher GC, Borutaite V. Mitochondrial disappearance from cells: a clue to the role of autophagy in programmed cell death and disease. Biochimie. 2002;84:233–40. doi: 10.1016/s0300-9084(02)01371-8. [DOI] [PubMed] [Google Scholar]
133.Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 2004;23:2891–906. doi: 10.1038/sj.onc.1207521. [DOI] [PubMed] [Google Scholar]
134.Ginsberg SD, Martin LJ. Ultrastructural analysis of the progression of neurodegeneration in the septum following fimbria-fornix transaction. Neuroscience. 1998;86:1259–72. doi: 10.1016/s0306-4522(98)00136-5. [DOI] [PubMed] [Google Scholar]
135.Ginsberg SD, Portera-Cailliau C, Martin LJ. Fimbria-fronix transection and excitotoxicity produce similar neurodegeneration in the septum. Neuroscience. 1999;88:1059–1071. doi: 10.1016/s0306-4522(98)00288-7. [DOI] [PubMed] [Google Scholar]
136.Martin LJ, Kaiser A, Price AC. Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis. J Neurobiol. 1999;40:185–201. [PubMed] [Google Scholar]
137.Al-Abdulla NA, Martin LJ. Apoptosis of retrogradely degenerating neurons occurs in association with accumulation of perikaryal mitochondria and oxidative damage to the nucleus. Am J Pathol. 1998;153:447–56. doi: 10.1016/S0002-9440(10)65588-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Martin LJ. An approach to experimental synaptic pathology using green fluorescent protein-transgenic mice and gene knockout mice: excitotoxic vulnerability of interneurons and moto-neurons is associated with mitochondrial accumulation and mediated by the mitochondrial permeability transition pore. Toxicol Pathol. 2011;39(1):220–33. doi: 10.1177/0192623310389475. [DOI] [PMC free article] [PubMed] [Google Scholar]
139.Clarke PGH. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol. 1990;181:195–213. doi: 10.1007/BF00174615. [DOI] [PubMed] [Google Scholar]
140.Schweichel JU, Merker HJ. The morphology of various types of cell death in prenatal tissues. Teratology. 1973;7:253–66. doi: 10.1002/tera.1420070306. [DOI] [PubMed] [Google Scholar]
141.Xue LZ, Fletcher GC, Tolkovsky AM. Autophagy is activated by apoptotic signaling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci. 1999;14:180–98. doi: 10.1006/mcne.1999.0780. [DOI] [PubMed] [Google Scholar]
142.Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N. A novel protein complex linking the δ2 glutamate receptor and autophagy: implications for neurodegeneration in Lurcher mice. Neuron. 2002;35:921–33. doi: 10.1016/s0896-6273(02)00861-9. [DOI] [PubMed] [Google Scholar]
143.Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;44:885–9. doi: 10.1038/nature04724. [DOI] [PubMed] [Google Scholar]
144.Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;44:880–4. doi: 10.1038/nature04723. [DOI] [PubMed] [Google Scholar]
145.Nakendra D, Tanaka A, Suen D-F, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803. doi: 10.1083/jcb.200809125. [DOI] [PMC free article] [PubMed] [Google Scholar]
146.Yuan J, Lipinski M, Degterev A. Diversity in the mechanisms of neuronal cell death. Neuron. 2003;40:401–13. doi: 10.1016/s0896-6273(03)00601-9. [DOI] [PubMed] [Google Scholar]
147.Todde V, Veenhuis M, van der Klei IJ. Autophagy: principles and significance in health and disease. Biochim Biophys Acta. 2009;1792:3–13. doi: 10.1016/j.bbadis.2008.10.016. [DOI] [PubMed] [Google Scholar]
148.Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 2001;8:569–81. doi: 10.1038/sj.cdd.4400852. [DOI] [PubMed] [Google Scholar]
149.Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol. 2002;157:455–68. doi: 10.1083/jcb.200109094. [DOI] [PMC free article] [PubMed] [Google Scholar]
150.Liange XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586–96. doi: 10.1128/jvi.72.11.8586-8596.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
151.Ogier-Denis E, Codogno P. Autophagy: a barrier or an adaptive response to cancer. Biochim Biophys Acta. 2003;1603:113–28. doi: 10.1016/s0304-419x(03)00004-0. [DOI] [PubMed] [Google Scholar]
152.Varadi A, Johnson-Cadwell LI, Cirulli V, Yoon Y, Allan VJ, Rutter GA. Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1. J Cell Sci. 2004;117:4389–400. doi: 10.1242/jcs.01299. [DOI] [PubMed] [Google Scholar]
153.Karbowski M, Lee Y-L, Gaume B, Jeong S-Y, Frank S, Nechushtan A, et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol. 2002;159:931–8. doi: 10.1083/jcb.200209124. [DOI] [PMC free article] [PubMed] [Google Scholar]
154.Davis AF, Clayton DA. In situ localization of mitochondrial DNA replication in intact mammalian cells. J Cell Biol. 1996;135:883–93. doi: 10.1083/jcb.135.4.883. [DOI] [PMC free article] [PubMed] [Google Scholar]
155.Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science. 2003;299:896–9. doi: 10.1126/science.1079368. [DOI] [PubMed] [Google Scholar]
156.Katzman R. Education and the prevalence of dementia and Alzheimer's disease. Neurology. 1993;43:13–20. doi: 10.1212/wnl.43.1_part_1.13. [DOI] [PubMed] [Google Scholar]
157.Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA. 1989;262:2551–6. [PubMed] [Google Scholar]
158.McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services task force on Alzheimer's disease. Neurology. 1984;34:939–44. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
159.Olshansky SJ, Carnes BA, Cassel CK. The aging of the human species. Sci Am. 1993;268:46–52. doi: 10.1038/scientificamerican0493-46. [DOI] [PubMed] [Google Scholar]
160.Minati L, Edginton T, Bruzzone MG, Giaccone G. Current concepts in Alzheimer's disease: a multidisciplinary review. Am J Alz Dis Other Dem. 2009;24:95–121. doi: 10.1177/1533317508328602. [DOI] [PMC free article] [PubMed] [Google Scholar]
161.Chartier-Harlin M-C, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature. 1991;353:844–6. doi: 10.1038/353844a0. [DOI] [PubMed] [Google Scholar]
162.Tilley L, Morgan K, Kalsheker N. Genetic risk factors for Alzheimer's disease. J Clin Pathol Mol Pathol. 1998;51:293–304. doi: 10.1136/mp.51.6.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
163.Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991;349:704–6. doi: 10.1038/349704a0. [DOI] [PubMed] [Google Scholar]
164.Naruse S, Igarashi S, Kobayashi H, Aoki K, Inuzuka T, Kaneko K, et al. Mis-sense mutation Val->Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet. 1991;337:978–9. doi: 10.1016/0140-6736(91)91612-x. [DOI] [PubMed] [Google Scholar]
165.Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, et al. Mutations of the presenilin 1 gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995;4:2373–7. doi: 10.1093/hmg/4.12.2373. [DOI] [PubMed] [Google Scholar]
166.Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375:754–60. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar]
167.Kalaria RN. Dementia comes of age in the developing world. Lancet. 2003;361:888–9. doi: 10.1016/S0140-6736(03)12783-3. [DOI] [PubMed] [Google Scholar]
168.Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer's disease. Annu Rev Med. 1996;47:387–400. doi: 10.1146/annurev.med.47.1.387. [DOI] [PubMed] [Google Scholar]
169.Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, DeLong MR. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215:1237–9. doi: 10.1126/science.7058341. [DOI] [PubMed] [Google Scholar]
170.Gomez-Isla T, Price JL, McKeel DW, Jr., Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci. 1996;16:4491–500. doi: 10.1523/JNEUROSCI.16-14-04491.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
171.Mouton PR, Martin LJ, Calhoun ME, Dal Forno G, Price DL. Cognitive decline strongly correlates with cortical atrophy in Alzheimer's disease. Neurobiol Aging. 1998;19:371–7. doi: 10.1016/s0197-4580(98)00080-3. [DOI] [PubMed] [Google Scholar]
172.West MJ, Kawas CH, Martin LJ, Troncoso JC. The CA1 region of the human hippocampus is a hot spot in Alzheimer's disease. Annu NY Acad Sci. 2000;908:255–9. doi: 10.1111/j.1749-6632.2000.tb06652.x. [DOI] [PubMed] [Google Scholar]
173.Pelvig DP, Pakkenberg H, Regeur L, Oster S, Pakkenberg B. Neocortical glial cell numbers in Alzheimer's disease. A stereological study. Dement Geriatr Cogn Disord. 2003;16:212–9. doi: 10.1159/000072805. [DOI] [PubMed] [Google Scholar]
174.Troncoso JC, Cataldo AM, Nixon RA, Barnett JL, Lee MK, Checler F, et al. Neuropathology of preclinical and clinical late-onset Alzheimer's disease. Ann Neurol. 1998;43:673–6. doi: 10.1002/ana.410430519. [DOI] [PubMed] [Google Scholar]
175.Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau is a major antigenic component of paired helical filaments in Alzheimer's disease. Proc Natl Acad Sci USA. 1986;83:4044–8. doi: 10.1073/pnas.83.11.4044. [DOI] [PMC free article] [PubMed] [Google Scholar]
176.Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6. doi: 10.1126/science.1072994. [DOI] [PubMed] [Google Scholar]
177.Sze C-I, Bi H, Kleinschmidt-DeMasters BK, Filley CM, Martin LJ. N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer's disease. J Neurol Sci. 2001;182:151–9. doi: 10.1016/s0022-510x(00)00467-6. [DOI] [PubMed] [Google Scholar]
178.Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat Neurosci. 2002;5:1039–42. doi: 10.1038/nn936. [DOI] [PubMed] [Google Scholar]
179.Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxi-city. J Neurosci. 1993;12:376–89. doi: 10.1523/JNEUROSCI.12-02-00376.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
180.Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008;14:45–53. doi: 10.1016/j.molmed.2007.12.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
181.DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64. doi: 10.1002/ana.410270502. [DOI] [PubMed] [Google Scholar]
182.Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80. doi: 10.1002/ana.410300410. [DOI] [PubMed] [Google Scholar]
183.Martin LJ, Pardo CA, Cork LC, Price DL. Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am J Pathol. 1994;145:1358–81. [PMC free article] [PubMed] [Google Scholar]
184.Sze C-I, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer's disease. J Neuropathol Exp Neurol. 1997;56:933–94. doi: 10.1097/00005072-199708000-00011. [DOI] [PubMed] [Google Scholar]
185.Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298:789–91. doi: 10.1126/science.1074069. [DOI] [PubMed] [Google Scholar]
186.Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science. 1989;245:417–20. doi: 10.1126/science.2474201. [DOI] [PubMed] [Google Scholar]
187.Younkin SG. Evidence that Abeta 42 is the real culprit in Alzheimer's disease. Ann Neurol. 1995;37:287–8. doi: 10.1002/ana.410370303. [DOI] [PubMed] [Google Scholar]
188.Fath T, Eidenmuller J, Brandt R. Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease. J Neurosci. 2002;22:9733–41. doi: 10.1523/JNEUROSCI.22-22-09733.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
189.Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to β-amyloid-induced neurotoxicity. Proc Natl Acad Sci USA. 2002;99:6364–9. doi: 10.1073/pnas.092136199. [DOI] [PMC free article] [PubMed] [Google Scholar]
190.Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol. 2003;161:41–54. doi: 10.1083/jcb.200207030. [DOI] [PMC free article] [PubMed] [Google Scholar]
191.Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006;26:9057–68. doi: 10.1523/JNEUROSCI.1469-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
192.Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006;15:1437–49. doi: 10.1093/hmg/ddl066. [DOI] [PubMed] [Google Scholar]
193.Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease. Science. 2004;304:448–52. doi: 10.1126/science.1091230. [DOI] [PubMed] [Google Scholar]
194.Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med. 2008;14:1097–105. doi: 10.1038/nm.1868. [DOI] [PMC free article] [PubMed] [Google Scholar]
195.Duyckaerts C, Potier MC, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol. 2008;115:5–38. doi: 10.1007/s00401-007-0312-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
196.Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, et al. Incidence of Parkinson's disease: variations by age, gender and race ethnicity. Am J Epidemol. 2003;157:1015–22. doi: 10.1093/aje/kwg068. [DOI] [PubMed] [Google Scholar]
197.Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79:368–76. doi: 10.1136/jnnp.2007.131045. [DOI] [PubMed] [Google Scholar]
198.Lowe J, Lennox G, Leigh PN. Disorders of movement and system degeneration. In: Graham DI, Lantos PL, editors. Greenfields neuropathology. Arnold; London: 1997. pp. 281–366. [Google Scholar]
199.Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24:197–211. doi: 10.1016/s0197-4580(02)00065-9. [DOI] [PubMed] [Google Scholar]
200.Martin LJ. Neurodegenerative disorders of the human brain and spinal cord. In: Ramachandran VS, editor. Encyclopedia of the human brain. Vol. 3. Elsevier Science; Amsterdam: 2002. pp. 441–63. [Google Scholar]
201.Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001;2:492–501. doi: 10.1038/35081564. [DOI] [PubMed] [Google Scholar]
202.Ascherio A, Chen H, Weisskopf MG, O'Reilly E, McCullough ML, Calle EE, et al. Pesticide exposure and risk for Parkinson's disease. Ann Neurol. 2006;60:197–203. doi: 10.1002/ana.20904. [DOI] [PubMed] [Google Scholar]
203.Schapira AHV. Etiology of Parkinson's disease. Neurology. 2006;66(Suppl. 4):S10–23. doi: 10.1212/wnl.66.10_suppl_4.s10. [DOI] [PubMed] [Google Scholar]
204.Shimohama S, Swada H, Kitamura Y, Taniguchi T. Disease model: Parkinson's disease. Trends Mol Med. 2003;9:360–5. doi: 10.1016/s1471-4914(03)00117-5. [DOI] [PubMed] [Google Scholar]
205.Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science. 1997;276:2045–7. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
206.Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science. 2003;302:841. doi: 10.1126/science.1090278. [DOI] [PubMed] [Google Scholar]
207.Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, et al. The ubiquitin pathway in Parkinson's disease. Nature. 1998;395:451–2. doi: 10.1038/26652. [DOI] [PubMed] [Google Scholar]
208.Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299:256–9. doi: 10.1126/science.1077209. [DOI] [PubMed] [Google Scholar]
209.Hatano Y, Li Y, Sato K, Asakawa S, Yamamura Y, Tomiyama H, et al. Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol. 2004;56:424–7. doi: 10.1002/ana.20251. [DOI] [PubMed] [Google Scholar]
210.Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8. doi: 10.1038/33416. [DOI] [PubMed] [Google Scholar]
211.Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert A, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004;304:1158–60. doi: 10.1126/science.1096284. [DOI] [PubMed] [Google Scholar]
212.Paisán-Ruíz C, Jain S, Whitney Evans E, Gilks WP, Simón J, van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004;44:595–600. doi: 10.1016/j.neuron.2004.10.023. [DOI] [PubMed] [Google Scholar]
213.Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–7. doi: 10.1016/j.neuron.2004.11.005. [DOI] [PubMed] [Google Scholar]
214.Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38:1184–91. doi: 10.1038/ng1884. [DOI] [PubMed] [Google Scholar]
215.Lesuisse C, Martin LJ. Long-term culture of mouse cortical neurons as a model for neuronal development, aging, and death. J Neurobiol. 2002;51:9–23. doi: 10.1002/neu.10037. [DOI] [PubMed] [Google Scholar]
216.Maroteaux L, Campanelli JT, Scheller RH. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminals. J Neurosci. 1998;8:2804–15. doi: 10.1523/JNEUROSCI.08-08-02804.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
217.Murphy DD, Rueter SM, Trojanowski JQ, Lee VMY. Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000;20:3214–20. doi: 10.1523/JNEUROSCI.20-09-03214.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
218.Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, et al. Double knockout mice for α- and β-synucleins: effect on synaptic functions. Proc Natl Acad Sci USA. 2004;101:14966–71. doi: 10.1073/pnas.0406283101. [DOI] [PMC free article] [PubMed] [Google Scholar]
219.Gurevicine I, Gurevicius K, Tanila H. Role of α-synuclein in synaptic glutamate release. Neurobiol Dis. 2007;28:83–9. doi: 10.1016/j.nbd.2007.06.016. [DOI] [PubMed] [Google Scholar]
220.Liu S, Fa M, Ninan I, Trinchese F, Dauer W, Aranico O. α-Synuclein involvement in hippocampal synaptic plasticity: role of NO, cGMP, cGK and CAMKII. Eur J Neurosci. 2007;25:3583–96. doi: 10.1111/j.1460-9568.2007.05569.x. [DOI] [PubMed] [Google Scholar]
221.Fortin DL, Nemani VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH. Neural activity control the synaptic accumulation of α-synuclein. J Neurosci. 2005;25:10913–21. doi: 10.1523/JNEUROSCI.2922-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
222.Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudholf TC. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell. 2005;123:383–96. doi: 10.1016/j.cell.2005.09.028. [DOI] [PubMed] [Google Scholar]
223.Gallardo G, Schluter OM, Sudhof TC. A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides. Nat Neurosci. 2008;11:301–8. doi: 10.1038/nn2058. [DOI] [PubMed] [Google Scholar]
224.Serpell LC, Berriman J, Jakes M, Goedert M, Crowther RA. Fiber diffraction of synthetic alpha synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci USA. 2000;97:4897–902. doi: 10.1073/pnas.97.9.4897. [DOI] [PMC free article] [PubMed] [Google Scholar]
225.Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT., Jr. Acceleration of oligomerization, not fibrilization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA. 2000;97:571–6. doi: 10.1073/pnas.97.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
226.Caughey B, Lansbury PT. Protofibrils, pores, fibril, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267–98. doi: 10.1146/annurev.neuro.26.010302.081142. [DOI] [PubMed] [Google Scholar]
227.Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, et al. Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2000;157:401–10. doi: 10.1016/s0002-9440(10)64553-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
228.Junn E, Mouradian MM. Human α-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett. 2002;320:146–50. doi: 10.1016/s0304-3940(02)00016-2. [DOI] [PubMed] [Google Scholar]
229.Tabrizi SJ, Orth M, Wilkinson JM, Taanman JW, Warner TT, Cooper JM, et al. Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity. Hum Mol Genet. 2000;9:2683–9. doi: 10.1093/hmg/9.18.2683. [DOI] [PubMed] [Google Scholar]
230.Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee WM-Y. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron. 2002;34:521–33. doi: 10.1016/s0896-6273(02)00682-7. [DOI] [PubMed] [Google Scholar]
231.Giasson BI, Duda JE, Murray IVJ, Chen Q, Souza JM, Hurtig HI, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000;290:985–9. doi: 10.1126/science.290.5493.985. [DOI] [PubMed] [Google Scholar]
232.Ischiropoulos H. Oxidative modification of alpha-synuclein. Annu NY Acad Sci. 2003;991:93–100. doi: 10.1111/j.1749-6632.2003.tb07466.x. [DOI] [PubMed] [Google Scholar]
233.Wilkinson KD, Lee KM, Deshpande S, Duerken-Hughes P, Boss JM, Pohl J. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl terminal hydrolase. Science. 1989;246:670–3. doi: 10.1126/science.2530630. [DOI] [PubMed] [Google Scholar]
234.Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–79. doi: 10.1146/annurev.biochem.67.1.425. [DOI] [PubMed] [Google Scholar]
235.Lansbury PT, Jr., Brice A. Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr Opin Cell Biol. 2002;14:653–60. doi: 10.1016/s0955-0674(02)00377-0. [DOI] [PubMed] [Google Scholar]
236.McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shahidharan P, Jennert P, et al. Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem. 2002;81:301–6. doi: 10.1046/j.1471-4159.2002.00821.x. [DOI] [PubMed] [Google Scholar]
237.Imai Y, Takahashi R. How do Parkin mutations result in neurodegeneration? Curr Opin Neurobiol. 2004;14:384–9. doi: 10.1016/j.conb.2004.04.002. [DOI] [PubMed] [Google Scholar]
238.Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, et al. Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene. Biochem Biophys Res Commun. 1998;249:754–8. doi: 10.1006/bbrc.1998.9134. [DOI] [PubMed] [Google Scholar]
239.Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci USA. 2005;102:5703–8. doi: 10.1073/pnas.0500617102. [DOI] [PMC free article] [PubMed] [Google Scholar]
240.Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet. 2005;14:3477–92. doi: 10.1093/hmg/ddi377. [DOI] [PubMed] [Google Scholar]
241.Unoki M, Nakamura Y. Growth-suppressive effects of BPOZ and RGR2, two genes involved in the PTEN signaling pathway. Oncogene. 2001;20:4457–65. doi: 10.1038/sj.onc.1204608. [DOI] [PubMed] [Google Scholar]
242.Taymans J-M, Van den Haute C, Baekelandt V. Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem. 2006;98:951–61. doi: 10.1111/j.1471-4159.2006.03919.x. [DOI] [PubMed] [Google Scholar]
243.Weihofen A, Thomas KJ, Ostazewski BL, Cooksen MR, Selkoe DJ. Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry. 2009;48:2045–52. doi: 10.1021/bi8019178. [DOI] [PMC free article] [PubMed] [Google Scholar]
244.Deng H, Jankovic J, Guo Y, Xie W, Le W. Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun. 2005;337:1133–8. doi: 10.1016/j.bbrc.2005.09.178. [DOI] [PubMed] [Google Scholar]
245.Marongiu R, Spencer B, Crews L, Adame A, Patrick C, Trejo M, et al. Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. J Neurochem. 2009;108:1561–74. doi: 10.1111/j.1471-4159.2009.05932.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
246.Wilson MA, Collins JL, Hod Y, Ringe D, Petsko GA. The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. Proc Natl Acad Sci USA. 2003;100:9256–61. doi: 10.1073/pnas.1133288100. [DOI] [PMC free article] [PubMed] [Google Scholar]
247.Shang H, Lang D, Jean-Marc B, Kaelin-Lang A. Localization of DJ-1 mRNA in the mouse brain. Neurosci Lett. 2004;367:273–7. doi: 10.1016/j.neulet.2004.06.002. [DOI] [PubMed] [Google Scholar]
248.Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA. 2004;101:9103–8. doi: 10.1073/pnas.0402959101. [DOI] [PMC free article] [PubMed] [Google Scholar]
249.Miller DW, Ahmad R, Hague S, Baptista MJ, Canet-Aviles R, McLendon C, et al. L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system. J Biol Chem. 2003;278:36588–95. doi: 10.1074/jbc.M304272200. [DOI] [PubMed] [Google Scholar]
250.Takahashi-Niki K, Niki T, Taira T, Iguchi-Ariga SM, Ariga H. Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients. Biochem Biophys Res Commun. 2004;320:389–97. doi: 10.1016/j.bbrc.2004.05.187. [DOI] [PubMed] [Google Scholar]
251.Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L. LRRK2 expression linked to dopamine-innervated areas. Ann Neurol. 2006;59:714–9. doi: 10.1002/ana.20808. [DOI] [PubMed] [Google Scholar]
252.Melrose H, Lincoln S, Tyndall G, Dickson D, Farrer M. Anatomical localization of leucine-rich repeat kinase 2 mouse brain. Neuroscience. 2006;139:791–4. doi: 10.1016/j.neuroscience.2006.01.017. [DOI] [PubMed] [Google Scholar]
253.Iaccarino C, Crosio C, Vitale C, Sanna G, Carri MT, Barone P. Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet. 2007;16:1319–26. doi: 10.1093/hmg/ddm080. [DOI] [PubMed] [Google Scholar]
254.Ho CC-Y, Rideout HJ, Ribe E, Troy CM, Dauer WT. The Parkinson's disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci. 2009;29:1011–6. doi: 10.1523/JNEUROSCI.5175-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
255.Goldberg MS, Fleming SM, Palacino JJ, Capedam C, Lam HA, Bhatnagar A, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 2003;278:43628–35. doi: 10.1074/jbc.M308947200. [DOI] [PubMed] [Google Scholar]
256.Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA. 2005;102:2174–9. doi: 10.1073/pnas.0409598102. [DOI] [PMC free article] [PubMed] [Google Scholar]
257.Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004;279:18614–22. doi: 10.1074/jbc.M401135200. [DOI] [PubMed] [Google Scholar]
258.Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Ding Y, et al. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem. 2005;280:21418–26. doi: 10.1074/jbc.M413955200. [DOI] [PubMed] [Google Scholar]
259.Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada Y, Costa C, et al. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial parkinsonism-linked gene DJ-1. Neuron. 2005;45:489–96. doi: 10.1016/j.neuron.2005.01.041. [DOI] [PubMed] [Google Scholar]
260.Lu X-H, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, et al. Bacterial artificial chromosome transgenic mice expressing a truncated mutant Parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of protein-ase K-resistant α-synuclein. J Neurosci. 2009;29:1962–76. doi: 10.1523/JNEUROSCI.5351-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
261.Gispert S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, et al. Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence or aggregate formation. Mol Cell Neurosci. 2003;24:419–29. doi: 10.1016/s1044-7431(03)00198-2. [DOI] [PubMed] [Google Scholar]
262.Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Schindzielorz A, et al. Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha-synuclein in human and transgenic mouse brain. J Neurosci. 2000;20:6365–73. doi: 10.1523/JNEUROSCI.20-17-06365.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
263.Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, et al. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic!mice. Proc Natl Acad Sci USA. 2002;99:8968–73. doi: 10.1073/pnas.132197599. [DOI] [PMC free article] [PubMed] [Google Scholar]
264.Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science. 2000;287:1265–9. doi: 10.1126/science.287.5456.1265. [DOI] [PubMed] [Google Scholar]
265.Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuetzer C, Gainetdinov RR, Caron MG, et al. Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol. 2002;175:35–48. doi: 10.1006/exnr.2002.7882. [DOI] [PubMed] [Google Scholar]
266.van der Putten H, Wiederhold K-H, Probst A, Barbieri S, Mistl C, Danner S, et al. Neuropathology in mice expressing human α-synuclein. J Neurosci. 2000;20:6021–9. doi: 10.1523/JNEUROSCI.20-16-06021.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
267.Wakamatsu M, Ishii A, Iwata S, Sakagami J, Ukai Y, Ono M, et al. Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein. Neurobiol Aging. 2008;29:547–85. doi: 10.1016/j.neurobiolaging.2006.11.017. [DOI] [PubMed] [Google Scholar]
268.Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, et al. Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci. 2006;26:41–50. doi: 10.1523/JNEUROSCI.4308-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
269.Lieberman AR. The axon reaction: a review of the principal features of perikaryal responses to axon injury. Int Rev Neurobiol. 1971;14:49–124. doi: 10.1016/s0074-7742(08)60183-x. [DOI] [PubMed] [Google Scholar]
270.Poon HF, Frasier M, Shreve N, Calabrese V, Wolozin B, Butterfield DA. Mitochondrial associated metabolic proteins are selectively oxidized in A30P α-synuclein transgenic mice—a model of familial Parkinson's disease. Neurobiol Dis. 2005;18:492–8. doi: 10.1016/j.nbd.2004.12.009. [DOI] [PubMed] [Google Scholar]
271.Turnbull S, Tabner BJ, El-Agnaf OM, Moore S, Davies Y, Allsop D. Alpha-synuclein implicated in Parkinson's disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med. 2001;30:1163–70. doi: 10.1016/s0891-5849(01)00513-5. [DOI] [PubMed] [Google Scholar]
272.Paxinou E, Chen Q, Weisse M, Giasson BI, Norris EH, Rueter SM, et al. Induction of alpha-synuclein aggregation by intracellular nitrative insult. J Neurosci. 2001;21:8053–61. doi: 10.1523/JNEUROSCI.21-20-08053.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
273.Souza JM, Giasson BI, Chen Q, Lee VM-Y, Ischiropoulos H. Dityrosine cross-linking promotes formation of stable α-synuclein polymers. J Biol Chem. 2000;265:18344–9. doi: 10.1074/jbc.M000206200. [DOI] [PubMed] [Google Scholar]
274.Martin LJ, Liu Z, Chen K, Price AC, Pan Y, Swaby JA, et al. Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J Comp Neurol. 2007;500:20–46. doi: 10.1002/cne.21160. [DOI] [PubMed] [Google Scholar]
275.Chen K, Northington FJ, Martin LJ. Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice. Brain Struct Funct. 2010;214:219–34. doi: 10.1007/s00429-009-0226-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
276.Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001;344:1688–700. doi: 10.1056/NEJM200105313442207. [DOI] [PubMed] [Google Scholar]
277.Sathasivam S, Ince PG, Shaw PJ. Apoptosis in amyotrophic lateral sclerosis: a review of the evidence. Neuropathol Appl Neurobiol. 2001;27:257–74. doi: 10.1046/j.0305-1846.2001.00332.x. [DOI] [PubMed] [Google Scholar]
278.Stephens B, Guiloff RJ, Navarrete R, Newman P, Nikhar N, Lewis P. Widespread loss of neuronal populations in spinal ventral horn in sporadic motor neuron disease. A morphometric study. J Neurol Sci. 2006;244:41–58. doi: 10.1016/j.jns.2005.12.003. [DOI] [PubMed] [Google Scholar]
279.Maekawa S, Al-Sarraj S, Kibble M, Landau S, Parnavelas J, Cotter D, et al. Cortical selective vulnerability in motor neurons disease: a morphometric study. Brain. 2004;127:1237–51. doi: 10.1093/brain/awh132. [DOI] [PubMed] [Google Scholar]
280.Zoccolella S, Santamato A, Lamberti P. Current and emerging treatments for amyotrophic lateral sclerosis. Neuropsychiatr Dis Treat. 2009;5:577–95. doi: 10.2147/ndt.s7788. [DOI] [PMC free article] [PubMed] [Google Scholar]
281.Kabashi E, Valdmains PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40:572–4. doi: 10.1038/ng.132. [DOI] [PubMed] [Google Scholar]
282.Deng H-X, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung W-Y, et al. Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science. 1993;261:1047–51. doi: 10.1126/science.8351519. [DOI] [PubMed] [Google Scholar]
283.Vance C, Rogelj B, Hortobagyi T, de Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323:1208–11. doi: 10.1126/science.1165942. [DOI] [PMC free article] [PubMed] [Google Scholar]
284.Schymick JC, Talbot K, Traynor GJ. Genetics of amyotrophic lateral sclerosis. Hum Mol Genet. 2007;16:R233–42. doi: 10.1093/hmg/ddm215. [DOI] [PubMed] [Google Scholar]
285.Chow CY, Lander JE, Bergren SK, Sapp PC, Grant AE, Jones JM, et al. Deleterious variants of FIG4, a phosphoinositade phosphatase, in patients with ALS. Am J Hum Genet. 2009;84:85–8. doi: 10.1016/j.ajhg.2008.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
286.Sasaki S, Iwata M. Ultrastructural changes of synapses of Betz cell in patients with amyotrophic lateral sclerosis. Neurosci Lett. 1999;268:29–32. doi: 10.1016/s0304-3940(99)00374-2. [DOI] [PubMed] [Google Scholar]
287.Menzies FM, Ince PG, Shaw PJ. Mitochondrial involvement in amyotrophic lateral sclerosis. Neurochem Int. 2002;40:543–51. doi: 10.1016/s0197-0186(01)00125-5. [DOI] [PubMed] [Google Scholar]
288.Comi GP, Bordoni A, Salani S, Franeschina L, Sciacco M, Prelle A, et al. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann Neurol. 1998;43:110–6. doi: 10.1002/ana.410430119. [DOI] [PubMed] [Google Scholar]
289.Borthwick GM, Taylo RW, Walls TJ, Tonska K, Taylor GA, Shaw PJ, et al. Motor neuron disease in a patient with a mitochondrial tRNAIle mutation. Ann Neurol. 2006;59:570–4. doi: 10.1002/ana.20758. [DOI] [PubMed] [Google Scholar]
290.Mawrin C, Kirches E, Krause G, Wiedemann FR, Vorwerk CK, Bogerts B, et al. Single-cell analysis of mtDNA levels in sporadic amyotrophic lateral sclerosis. Neuroreport. 2004;15:939–43. doi: 10.1097/00001756-200404290-00002. [DOI] [PubMed] [Google Scholar]
291.Bender A, Krishnan KJ, Morris CM, Taylor GA, Reve AK, Perry RP, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson's disease. Nat Genet. 2006;38:515–7. doi: 10.1038/ng1769. [DOI] [PubMed] [Google Scholar]
292.Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet. 2006;38:518–20. doi: 10.1038/ng1778. [DOI] [PubMed] [Google Scholar]
293.Babcock D, Hille B. Mitochondrial oversight of cellular Ca2+ signaling. Curr Opin Neurobiol. 1998;8:398–404. doi: 10.1016/s0959-4388(98)80067-6. [DOI] [PubMed] [Google Scholar]
294.Siklos L, Engelhardt J, Harat Y, Smith RG, Joo F, Appel SH. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol. 1996;39:203–16. doi: 10.1002/ana.410390210. [DOI] [PubMed] [Google Scholar]
295.Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med. 1992;326:1464–8. doi: 10.1056/NEJM199205283262204. [DOI] [PubMed] [Google Scholar]
296.Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995;38:73–84. doi: 10.1002/ana.410380114. [DOI] [PubMed] [Google Scholar]
297.Heath PR, Tomkins J, Ince PG, Shaw PJ. Quantitative assessment of AMPA receptor mRNA in human spinal motor neurons isolated by laser capture microdissection. Neuroreport. 2002;13:1753–7. doi: 10.1097/00001756-200210070-00012. [DOI] [PubMed] [Google Scholar]
298.Kwak S, Kawahara Y. Deficient RNA editing of GluR2 and neuronal death in amyotrophic lateral sclerosis. J Mol Med. 2005;83:110–20. doi: 10.1007/s00109-004-0599-z. [DOI] [PubMed] [Google Scholar]
299.Chang DTW, Reynolds IJ. Mitochondrial trafficking and morphology in healthy and injured neurons. Prog Brain Res. 2006;80:241–68. doi: 10.1016/j.pneurobio.2006.09.003. [DOI] [PubMed] [Google Scholar]
300.Hansson MJ, Mansson R, Morota S, Uchino H, Kallur T, Sumi T, et al. Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition. Free Radic Biol Med. 2008;45:284–94. doi: 10.1016/j.freeradbiomed.2008.04.021. [DOI] [PubMed] [Google Scholar]
301.Bergmann F, Keller BU. Impact of mitochondrial inhibition on excitability and cytosolic Ca2+ levels in brainstem motoneurones. J Physiol. 2004;555:45–59. doi: 10.1113/jphysiol.2003.053900. [DOI] [PMC free article] [PubMed] [Google Scholar]
302.Beal MF. Oxidatively modified protein in aging and disease. Free Radic Biol Med. 2002;32:797–803. doi: 10.1016/s0891-5849(02)00780-3. [DOI] [PubMed] [Google Scholar]
303.Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997;69:2064–74. doi: 10.1046/j.1471-4159.1997.69052064.x. [DOI] [PubMed] [Google Scholar]
304.Abe K, Pan L-H, Watanabe M, Kato T, Itoyama Y. Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis. Neurosci Lett. 1995;199:152–4. doi: 10.1016/0304-3940(95)12039-7. [DOI] [PubMed] [Google Scholar]
305.Beal MF, Ferrante RJ, Browne SE, Matthews RT, Kowall NW, Brown RH., Jr. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol. 1997;42:644–54. doi: 10.1002/ana.410420416. [DOI] [PubMed] [Google Scholar]
306.Sasaki S, Warita H, Abe K, Iwata M. Inducible nitric oxide synthase (iNOS) and nitrotyrosine immunoreactivity in the spinal cords of transgenic mice with mutant SOD1 gene. J Neuropathol Exp Neurol. 2001;60:839–46. doi: 10.1093/jnen/60.9.839. [DOI] [PubMed] [Google Scholar]
307.Browne SE, Bowling AC, Baik MJ, Gurney M, Brown RH, Jr., Beal MF. Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J Neurochem. 1998;71:281–7. doi: 10.1046/j.1471-4159.1998.71010281.x. [DOI] [PubMed] [Google Scholar]
308.Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol. 1999;46:787–90. doi: 10.1002/1531-8249(199911)46:5<787::aid-ana17>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
309.Vielhaber S, Kunz D, Winkler K, Wiedemann FR, Kirches E, Feistner H, et al. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain. 2000;123:1339–48. doi: 10.1093/brain/123.7.1339. [DOI] [PubMed] [Google Scholar]
310.Soraru G, Vergani L, Fedrizzi L, D'Ascenzo C, Polo A, Bernazzi B, et al. Activities of mitochondrial complexes correlate with nNOS amount in muscle from ALS patients. Neuropathol Appl Neurobiol. 2007;33:204–11. doi: 10.1111/j.1365-2990.2006.00791.x. [DOI] [PubMed] [Google Scholar]
311.Echaniz-Laguna A, Zoll J, Ponsot E, N'Guessan B, Tranchant C, Loeffler J-P, et al. Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: a temporal study in man. Exp Neurol. 2006;198:25–30. doi: 10.1016/j.expneurol.2005.07.020. [DOI] [PubMed] [Google Scholar]
312.Martin LJ. Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol. 1999;58:459–71. doi: 10.1097/00005072-199905000-00005. [DOI] [PubMed] [Google Scholar]
313.Martin LJ, Liu Z. Opportunities for neuroprotection in ALS using cell death mechanism rationales. Drug Discov Today. 2004;1:135–43. [Google Scholar]
314.Ginsberg SD, Hemby SE, Mufson EJ, Martin LJ. Cell and tissue microdissection in combination with genomic and proteomic profiling. In: Zaborszky L, Wouterlood FG, Lanciego JL, editors. Neuroanatomical tract-tracing 3, molecules, neurons, and systems. Springer; New York: 2006. pp. 109–41. [Google Scholar]
315.Martin LJ. p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis. Neurobiol Dis. 2000;7:613–22. doi: 10.1006/nbdi.2000.0314. [DOI] [PubMed] [Google Scholar]
316.Martin LJ. The apoptosis-necrosis cell death continuum in CNS development, injury and disease: contributions and mechanisms. In: Lo EH, Marwah J, editors. Neuroprotection. Prominent Press; Scottsdale, AZ: 2002. pp. 379–412. [Google Scholar]
317.Martin LJ, Price AC, Kaiser A, Shaikh AY, Liu Z. Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death. Int J Mol Med. 2000;5:3–13. doi: 10.3892/ijmm.5.1.3. [DOI] [PubMed] [Google Scholar]
318.Liu Z, Martin LJ. Motor neurons rapidly accumulate DNA single-strand breaks after in vitro exposure to nitric oxide and peroxynitrite and in vivo axotomy. J Comp Neurol. 2001;432:35–60. doi: 10.1002/cne.1087. [DOI] [PubMed] [Google Scholar]
319.Wong M, Martin LJ. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet. 2010;9:2284–302. doi: 10.1093/hmg/ddq106. [DOI] [PMC free article] [PubMed] [Google Scholar]
320.Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol. 2008;85:94–134. doi: 10.1016/j.pneurobio.2008.01.001. [DOI] [PubMed] [Google Scholar]
321.McCord JM, Fridovich I. Superoxide dismutase, an enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244:6049–55. [PubMed] [Google Scholar]
322.Rakhit R, Crow JP, Lepock JR, Kondejewski LH, Cashman NR, Chakrabartty A. Monomeric Cu, Zn-superoxide dismutase is a common misfolding intermediate in the oxidation models of sporadic and familial amyotrophic sclerosis. J Biol Chem. 2004;279:15499–504. doi: 10.1074/jbc.M313295200. [DOI] [PubMed] [Google Scholar]
323.Ferri A, Cozzolino M, Crosio C, Nencini M, Casciati A, Gralla EB, et al. Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. Proc Natl Acad Sci USA. 2006;103:13860–5. doi: 10.1073/pnas.0605814103. [DOI] [PMC free article] [PubMed] [Google Scholar]
324.Estévez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, Richardson GJ, et al. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science. 1999;286:2498–500. doi: 10.1126/science.286.5449.2498. [DOI] [PubMed] [Google Scholar]
325.Flanagan SW, Anderson RD, Ross MA, Oberley LW. Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Znsuperoxide dismutase. J Neurochem. 2002;81:170–7. doi: 10.1046/j.1471-4159.2002.00812.x. [DOI] [PubMed] [Google Scholar]
326.Bilsland LG, Nirmalananthan N, Yip J, Greensmith L, Duhcen MR. Expression of mutant SOD1G93A in astrocytes induces functional deficits in motoneuron mitochondria. J Neurochem. 2008;107:1271–83. doi: 10.1111/j.1471-4159.2008.05699.x. [DOI] [PubMed] [Google Scholar]
327.Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5. doi: 10.1126/science.8209258. [DOI] [PubMed] [Google Scholar]
328.Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol. 1994;145:1271–9. [PMC free article] [PubMed] [Google Scholar]
329.Chang Q, Martin LJ. Glycinergic innervation of motoneurons is deficient in amyotrophic lateral sclerosis mice: a confocal quantitative analysis. Am J Pathol. 2009;174:574–85. doi: 10.2353/ajpath.2009.080557. [DOI] [PMC free article] [PubMed] [Google Scholar]
330.Bendotti C, Calvaresi N, Chiveri L, Prelle A, Moggio M, Braga M, et al. Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity. J Neurol Sci. 2001;191:25–33. doi: 10.1016/s0022-510x(01)00627-x. [DOI] [PubMed] [Google Scholar]
331.Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995;14:1105–16. doi: 10.1016/0896-6273(95)90259-7. [DOI] [PubMed] [Google Scholar]
332.Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998;18:3241–50. doi: 10.1523/JNEUROSCI.18-09-03241.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
333.Jaarsma D, Rognoni F, van Duijn W, Verspaget HW, Haasdijk ED, Holstege JC. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. 2001;102:293–305. doi: 10.1007/s004010100399. [DOI] [PubMed] [Google Scholar]
334.Sasaki S, Warita H, Murakami T, Abe K, Iwata M. Ultrastructural study of mitochondria in the spinal cord of transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathol. 2004;107:461–74. doi: 10.1007/s00401-004-0837-z. [DOI] [PubMed] [Google Scholar]
335.Borchelt DR, Lee MK, Slunt HH, Guarnieri M, Xu Z-S, Wong PC, et al. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci USA. 1994;91:8292–6. doi: 10.1073/pnas.91.17.8292. [DOI] [PMC free article] [PubMed] [Google Scholar]
336.Yim MB, Kang J-H, Yim H-S, Kwak H-S, Chock PB, Stadtman ER. A gain-of-function of an amyotrophic lateral sclerosis-associated Cu, Zn-superoxide dismutase mutant: an enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. Proc Natl Acad Sci USA. 1996;93:5709–14. doi: 10.1073/pnas.93.12.5709. [DOI] [PMC free article] [PubMed] [Google Scholar]
337.Kabashi E, Valdmanis PN, Dion P, Rouleau GA. Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis? Ann Neurol. 2007;62:553–9. doi: 10.1002/ana.21319. [DOI] [PubMed] [Google Scholar]
338.Ezzi SA, Urushitani M, Julien J-P. Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J Neurochem. 2007;102:170–8. doi: 10.1111/j.1471-4159.2007.04531.x. [DOI] [PubMed] [Google Scholar]
339.Liochev SI, Fridovich I. Mutant Cu, Zn superoxide dismutases and familial amyotrophic lateral sclerosis: evaluation of oxidative hypotheses. Free Radic Biol Med. 2003;34:1383–9. doi: 10.1016/s0891-5849(03)00153-9. [DOI] [PubMed] [Google Scholar]
340.Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315–424. doi: 10.1152/physrev.00029.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
341.Andrus PK, Fleck TJ, Gurney ME, Hall ED. Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem. 1998;71:2041–8. doi: 10.1046/j.1471-4159.1998.71052041.x. [DOI] [PubMed] [Google Scholar]
342.Poon HF, Hensley K, Thongboonkerd V, Merchant ML, Lynn BC, Pierce WM, et al. Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—a model of familial amyotrophic lateral sclerosis. Free Radic Biol Med. 2005;39:435–62. doi: 10.1016/j.freeradbiomed.2005.03.030. [DOI] [PubMed] [Google Scholar]
343.Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide (SOD) in rat liver. J Biol Chem. 2001;276:38388–93. doi: 10.1074/jbc.M105395200. [DOI] [PubMed] [Google Scholar]
344.Higgins CMJ, Jung C, Ding H, Xu Z. Mutant Cu Zn Superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J Neurosci. 2002;22(RC215):1–6. doi: 10.1523/JNEUROSCI.22-06-j0001.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
345.Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, et al. Amyotrophic lateral sclerosis-associated SOD1 mutant protein bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004;43:19–30. doi: 10.1016/j.neuron.2004.06.021. [DOI] [PubMed] [Google Scholar]
346.Goldsteins G, Keksa-Goldsteine V, Ahtiniemi T, Jaronen M, Arens E, Akerman K, et al. Deleterious role of superoxide dismutase in the mitochondrial intermembrane space. J Biol Chem. 2008;283:8446–52. doi: 10.1074/jbc.M706111200. [DOI] [PubMed] [Google Scholar]
347.Higgins CM, Jung C, Xu Z. ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 2003;4:16. doi: 10.1186/1471-2202-4-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
348.De Vos KJ, Chapman AL, Tennant ME, Manser C, Tudor EL, Lau K-F, et al. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondrial content. Hum Mol Genet. 2007;16:2720–8. doi: 10.1093/hmg/ddm226. [DOI] [PMC free article] [PubMed] [Google Scholar]
349.Martin LJ, Chen K, Liu Z. Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation. J Neurosci. 2005;25:6449–59. doi: 10.1523/JNEUROSCI.0911-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
350.Siklos L, Engelhardt JI, Alexianu ME, Gurney ME, Siddique T, Appel SH. Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice. J Neuropathol Exp Neurol. 1998;57:571–87. doi: 10.1097/00005072-199806000-00005. [DOI] [PubMed] [Google Scholar]
351.Jaiswal MK, Keller BU. Cu/Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of mitochondria and perturbs Ca2+ homeostasis in SOD1G93A mice. Mol Pharmacol. 2009;75:478–89. doi: 10.1124/mol.108.050831. [DOI] [PubMed] [Google Scholar]
352.Nguyen KT, Garcia-Chacon LE, Barrett JN, Barrett EF, David G. The ψm depolarization that accompanies mitochondrial Ca2+ uptake is greater in mutant SOD1 than in wild-type mouse motor terminals. Proc Natl Acad Sci USA. 2009;106:2007–11. doi: 10.1073/pnas.0810934106. [DOI] [PMC free article] [PubMed] [Google Scholar]
353.Sasaki S, Shibata N, Komori T, Iwata M. iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis. Neurosci Lett. 2000;291:44–8. doi: 10.1016/s0304-3940(00)01370-7. [DOI] [PubMed] [Google Scholar]
354.Martin LJ. Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010;13:568–80. [PMC free article] [PubMed] [Google Scholar]
355.Kunz WS. Different metabolic properties of mitochondrial oxidative phosphorylation in different cell types—important implications for mitochondrial cytopathies. Exp Physiol. 2003;88(1):149–54. doi: 10.1113/eph8802512. [DOI] [PubMed] [Google Scholar]
356.Keep M, Elmér E, Fong KSK, Csiszar K. Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Brain Res. 2001;894:27–331. doi: 10.1016/s0006-8993(01)02012-1. [DOI] [PubMed] [Google Scholar]
357.Karlsson J, Fong KS, Hansson MJ, Elmer E, Csiszar K, Keep MF. Life span extension and reduced neuronal death after weekly intraventricular cyclosporine injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis. J Neurosurg. 2004;101:128–37. doi: 10.3171/jns.2004.101.1.0128. [DOI] [PubMed] [Google Scholar]
358.Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT. An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment. J Neurochem. 2004;88:821–6. doi: 10.1046/j.1471-4159.2003.02181.x. [DOI] [PubMed] [Google Scholar]
359.Bordet T, Buisson B, Michaud M, Drouot C, Galea P, Delaage P, et al. Identification and characterization of Cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007;322:709–20. doi: 10.1124/jpet.107.123000. [DOI] [PubMed] [Google Scholar]
360.Mills C, Makwana M, Wallace A, Benn S, Schmidt H, Tegeder I, et al. Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats. Eur J Neurosci. 2008;27:937–46. doi: 10.1111/j.1460-9568.2008.06065.x. [DOI] [PubMed] [Google Scholar]
361.Yan L-J, Sohal RS. Mitochondrial adenine nucleotide translocase is modified oxidatively during aging. Proc Natl Acad Sci USA. 1998;95:12896–901. doi: 10.1073/pnas.95.22.12896. [DOI] [PMC free article] [PubMed] [Google Scholar]
362.Prokai L, Yan L-J, Vera-Serrano JL, Stevens SM, Jr., Forster MJ. Mass spectrometry-based survey of age-associated protein carbonylation in rat brain mitochondria. J Mass Spectrom. 2007;42:1583–9. doi: 10.1002/jms.1345. [DOI] [PubMed] [Google Scholar]
363.Vieira HLA, Belzacq A-S, Haouzu D, Bernassola F, Cohen I, Jacotot E, et al. The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene. 2001;20:4305–16. doi: 10.1038/sj.onc.1204575. [DOI] [PubMed] [Google Scholar]
364.McStay GP, Clarke SJ, Halestrap AP. Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J. 2002;367:541–8. doi: 10.1042/BJ20011672. [DOI] [PMC free article] [PubMed] [Google Scholar]
365.Trumbull KA, Beckman JS. A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis. Antioxid Redox Signal. 2009;11:1627–39. doi: 10.1089/ars.2009.2574. [DOI] [PMC free article] [PubMed] [Google Scholar]
366.Costantini P, Belzacq A-S, Vieira HLA, Larochette N, de Pablo MA, Zamzami N, et al. Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis. Oncogene. 2000;19:307–14. doi: 10.1038/sj.onc.1203299. [DOI] [PubMed] [Google Scholar]
367.García N, Martínez-Abundis E, Pavón N, Correa F, Chávez E. Copper induces permeability transition through its interaction with the adenine nucleotide translocase. Cell Biol Int. 2007;31:893–9. doi: 10.1016/j.cellbi.2007.02.003. [DOI] [PubMed] [Google Scholar]
368.Grimm S, Brdiczka D. The permeability transition pore in cell death. Apoptosis. 2007;12:841–55. doi: 10.1007/s10495-007-0747-3. [DOI] [PubMed] [Google Scholar]
369.Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, et al. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc Natl Acad Sci USA. 2007;104:7558–63. doi: 10.1073/pnas.0702228104. [DOI] [PMC free article] [PubMed] [Google Scholar]
370.Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci USA. 2005;102:12005–10. doi: 10.1073/pnas.0505294102. [DOI] [PMC free article] [PubMed] [Google Scholar]
371.Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomized trial. Lancet Neurol. 2007;6:1045–53. doi: 10.1016/S1474-4422(07)70270-3. [DOI] [PubMed] [Google Scholar]
372.Simon-Sanchez J, Singleton AB. Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. Hum Mol Genet. 2008;17:1988–93. doi: 10.1093/hmg/ddn096. [DOI] [PMC free article] [PubMed] [Google Scholar]
373.Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton M, Sudhof TC. α-Synulcein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663–7. doi: 10.1126/science.1195227. [DOI] [PMC free article] [PubMed] [Google Scholar]
374.Garcia-Reitbock P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E, Ghetti B, et al. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain. 2010;133:2032–44. doi: 10.1093/brain/awq132. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R1] 1.Zorov DB, Isave NK, Plotnikov EY, Zorova LD, Stelmashook EV, Vasileva AK, et al. The mitochondrion as Janus Bifrons. Biochemistry (Mosc) 2007;72:1115–26. doi: 10.1134/s0006297907100094. [DOI] [PubMed] [Google Scholar]

[R2] 2.Halliwell B. Role of free radicals in the neurodegenerative diseases. Drugs Aging. 2001;18:685–716. doi: 10.2165/00002512-200118090-00004. [DOI] [PubMed] [Google Scholar]

[R3] 3.Nicholls DG. Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int J Biochem Cell Biol. 2002;34:1372–81. doi: 10.1016/s1357-2725(02)00077-8. [DOI] [PubMed] [Google Scholar]

[R4] 4.Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn of evolutionary medicine. Annu Rev Genet. 2002;39:359–407. doi: 10.1146/annurev.genet.39.110304.095751. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97–112. doi: 10.1146/annurev.bi.64.070195.000525. [DOI] [PubMed] [Google Scholar]

[R6] 6.Mungrue IN, Bredt DS, Stewart DJ, Husain M. From molecules to mammals: what's NOS got to do with it? Acta Physiol Scand. 2003;179:123–35. doi: 10.1046/j.1365-201X.2003.01182.x. [DOI] [PubMed] [Google Scholar]

[R7] 7.Martin LJ. Mitochondrial and cell death mechanisms in neurodegenerative disease. Pharmaceuticals. 2010;3:839–915. doi: 10.3390/ph3040839. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] 8.Delettre C, Lenaers G, Pelloquin L, Belenguer P, Hamel CP. OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol Genet Metab. 2002;75:97–107. doi: 10.1006/mgme.2001.3278. [DOI] [PubMed] [Google Scholar]

[R9] 9.Chen H, Chan DC. Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet. 2005;14:R283–9. doi: 10.1093/hmg/ddi270. [DOI] [PubMed] [Google Scholar]

[R10] 10.Brown MD, Voljavec AS, Lott MT, MacDolald I, Wallace DC. Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB J. 1992;6:2791–9. doi: 10.1096/fasebj.6.10.1634041. [DOI] [PubMed] [Google Scholar]

[R11] 11.Wong L-JC, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, et al. Molecular and clinical genetics of mitochondrial disease due to POLG mutations. Hum Mutat. 2008;29:E150–72. doi: 10.1002/humu.20824. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] 12.Goffart S, Cooper HM, Tyynismaa H, Wanrooij S, Suomalainen A, Spelbrink JN. Twinkle mutations associated with autosomal dominant progressive external opthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet. 2009;18:328–40. doi: 10.1093/hmg/ddn359. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] 13.Komaki H, Fukazawa T, Houzen H, Yoshida K, Nonaka I, Goto Y. A novel D104G mutation in the adenine nucleotide translocator 1 gene in autosomal dominant external opthalmoplegia patients with mitochondrial DNA with multiple deletions. Ann Neurol. 2002;51:645–8. doi: 10.1002/ana.10172. [DOI] [PubMed] [Google Scholar]

[R14] 14.Martin LJ, Al-Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera-Cailliau C. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull. 1998;46:281–309. doi: 10.1016/s0361-9230(98)00024-0. [DOI] [PubMed] [Google Scholar]

[R15] 15.Northington FJ, Graham EM, Martin LJ. Apoptosis in perinatal hypoxic-ischemic brain injury: how important is it and should it be inhibited? Brain Res Rev. 2005;50:244–57. doi: 10.1016/j.brainresrev.2005.07.003. [DOI] [PubMed] [Google Scholar]

[R16] 16.Martin LJ. The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis. Biochim Biophys Acta. 2010;1802:186–97. doi: 10.1016/j.bbadis.2009.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R17] 17.Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters JJ. Cyclophilin D as a drug target. Curr Med Chem. 2003;10:1485–506. doi: 10.2174/0929867033457160. [DOI] [PubMed] [Google Scholar]

[R18] 18.Crompton M. Mitochondria and aging: a role for the permeability transition? Aging Cell. 2004;3:3–6. doi: 10.1046/j.1474-9728.2003.00073.x. [DOI] [PubMed] [Google Scholar]

[R19] 19.Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol. 2009;46:821–31. doi: 10.1016/j.yjmcc.2009.02.021. [DOI] [PubMed] [Google Scholar]

[R20] 20.Bernardi P, Krauskopf A, Basso E, Petronilli V, Blalchy-Dyson E, Di Lisa F, et al. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J. 2006;273:2077–99. doi: 10.1111/j.1742-4658.2006.05213.x. [DOI] [PubMed] [Google Scholar]

[R21] 21.Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, et al. Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005;19:2040–1. doi: 10.1096/fj.05-3735fje. [DOI] [PubMed] [Google Scholar]

[R22] 22.Beckman JS, Carson M, Smith CD, Koppenol WH. ALS, SOD and peroxynitrite. Nature. 1993;364:548. doi: 10.1038/364584a0. [DOI] [PubMed] [Google Scholar]

[R23] 23.Martin LJ, Liu Z. DNA damage profiling in motor neurons: a single-cell analysis by comet assay. Neurochem Res. 2002;27:1089–100. doi: 10.1023/a:1020961006216. [DOI] [PubMed] [Google Scholar]

[R24] 24.Giulini C. Characterization and function of mitochondrial nitric-oxide synthase. Free Radic Biol Med. 2003;34:397–408. doi: 10.1016/s0891-5849(02)01298-4. [DOI] [PubMed] [Google Scholar]

[R25] 25.Brown GC, Borutaite V. Nitric oxide, cytochrome c, and mitochondria. Biochem Soc Symp. 1999;66:17–25. doi: 10.1042/bss0660017. [DOI] [PubMed] [Google Scholar]

[R26] 26.Choi DW. Cellular defences destroyed. Nature. 2005;433:696–8. doi: 10.1038/433696a. [DOI] [PubMed] [Google Scholar]

[R27] 27.Brown MR, Sullivan PG, Geddes JW. Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria. J Biol Chem. 2006;281:11658–68. doi: 10.1074/jbc.M510303200. [DOI] [PubMed] [Google Scholar]

[R28] 28.Soong NW, Hinton DR, Cortopassi G, Arnheim N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet. 1992;2:318–23. doi: 10.1038/ng1292-318. [DOI] [PubMed] [Google Scholar]

[R29] 29.Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet. 1992;2:324–9. doi: 10.1038/ng1292-324. [DOI] [PubMed] [Google Scholar]

[R30] 30.Driggers WJ, LeDoux SP, Wilson GL. Repair of oxidative damage within the mitochondrial DNA or RINr 38 cells. J Biol Chem. 1993;268:22042–5. [PubMed] [Google Scholar]

[R31] 31.Larsen NB, Rasmussen M, Rasmussen LJ. Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion. 2005;5:89–108. doi: 10.1016/j.mito.2005.02.002. [DOI] [PubMed] [Google Scholar]

[R32] 32.Szczesny B, Hazra TK, Papaconstantinou J, Mitra S, Boldogh I. Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci USA. 2003;100:10670–5. doi: 10.1073/pnas.1932854100. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R33] 33.Popp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics. 1996;36:449–58. doi: 10.1006/geno.1996.0490. [DOI] [PubMed] [Google Scholar]

[R34] 34.Gunawardena S, Goldstein LSB. Cargo-carrying motor vehicles on the neuronal highway: transport pathways and neurodegenerative disease. J Neurobiol. 2003;58:258–71. doi: 10.1002/neu.10319. [DOI] [PubMed] [Google Scholar]

[R35] 35.Chada SR, Hollenbeck PJ. Mitochondrial movement and positioning in axons: the role of growth factor signaling. J Exp Biol. 2003;206:1985–92. doi: 10.1242/jeb.00263. [DOI] [PubMed] [Google Scholar]

[R36] 36.Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, Harada A, et al. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell. 1998;93:1147–58. doi: 10.1016/s0092-8674(00)81459-2. [DOI] [PubMed] [Google Scholar]

[R37] 37.Ligon LA, Steward O. Role of microtubules and actin filaments in the movement of mitochondria in the axons and dendrites of cultured hippocampal neurons. J Comp Neurol. 2000;427:351–61. doi: 10.1002/1096-9861(20001120)427:3<351::aid-cne3>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]

[R38] 38.Pintoul GL, Filiano AJ, Brocard JB, Kress GJ, Reynolds IJ. Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J Neurosci. 2003;23:7881–8. doi: 10.1523/JNEUROSCI.23-21-07881.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R39] 39.Reynolds IJ, Malaiyandi LM, Coash M, Rintoul GL. Mitochondrial trafficking in neurons: a key variable in neurodegeneration? J Bioeng Biomembr. 2004;36:283–6. doi: 10.1023/B:JOBB.0000041754.78313.c2. [DOI] [PubMed] [Google Scholar]

[R40] 40.Miller KE, Sheetz MP. Axonal mitochondrial transport and potential are correlated. J Cell Sci. 2004;117:2791–804. doi: 10.1242/jcs.01130. [DOI] [PubMed] [Google Scholar]

[R41] 41.Tatebayashi Y, Haque N, Tung YC, Iqbal K, Grundke-Iqbal I. Role of tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport. J Cell Sci. 2004;117:1653–63. doi: 10.1242/jcs.01018. [DOI] [PubMed] [Google Scholar]

[R42] 42.Martin LJ. Neuronal cell death in nervous system development, disease, and injury. Int J Mol Med. 2001;7:455–78. [PubMed] [Google Scholar]

[R43] 43.Lockshin RA, Zakeri Z. Caspase-independent cell deaths. Curr Opin Cell Biol. 2002;14:727–33. doi: 10.1016/s0955-0674(02)00383-6. [DOI] [PubMed] [Google Scholar]

[R44] 44.Gilbert S. Developmental biology. Sinauer Associates; Sunderland: 2006. [Google Scholar]

[R45] 45.Ameisen JC. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ. 2002;9:367–93. doi: 10.1038/sj.cdd.4400950. [DOI] [PubMed] [Google Scholar]

[R46] 46.Metzstein MM, Stanfield GM, Horvitz HR. Genetics of programmed cell death in C. elegans: past, present and future. Trends Genet. 1998;14:410–6. doi: 10.1016/s0168-9525(98)01573-x. [DOI] [PubMed] [Google Scholar]

[R47] 47.Youle RJ, Strasser A. The Bcl-2 protein family: opposing activities that mediate cell death. Nat Rev. 2008;9:47–59. doi: 10.1038/nrm2308. [DOI] [PubMed] [Google Scholar]

[R48] 48.Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci. 1997;20:245–67. doi: 10.1146/annurev.neuro.20.1.245. [DOI] [PubMed] [Google Scholar]

[R49] 49.Cory S, Adams JM. The bcl-2 family: regulators of the cellular life-or-death switch. Nat Rev. 2002;2:647–56. doi: 10.1038/nrc883. [DOI] [PubMed] [Google Scholar]

[R50] 50.Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem. 1999;274:20049–52. doi: 10.1074/jbc.274.29.20049. [DOI] [PubMed] [Google Scholar]

[R51] 51.Nagata S. Fas ligand-induced apoptosis. Annu Rev Genet. 1999;33:29–55. doi: 10.1146/annurev.genet.33.1.29. [DOI] [PubMed] [Google Scholar]

[R52] 52.Levrero M, De Laurenzi V, Costanzo A, Sabatini S, Gong J, Wang JYJ, et al. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci. 2000;113:1661–70. doi: 10.1242/jcs.113.10.1661. [DOI] [PubMed] [Google Scholar]

[R53] 53.Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91:479–89. doi: 10.1016/s0092-8674(00)80434-1. [DOI] [PubMed] [Google Scholar]

[R54] 54.Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–57. doi: 10.1016/s0092-8674(00)80085-9. [DOI] [PubMed] [Google Scholar]

[R55] 55.Klein JA, Longo-Guess CM, Rossmann MP, Seburn RE, Hurd RE, Frankel WN, et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002;419:367–74. doi: 10.1038/nature01034. [DOI] [PubMed] [Google Scholar]

[R56] 56.Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilentei L, et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem. 2002;277:432–4538. doi: 10.1074/jbc.M109721200. [DOI] [PubMed] [Google Scholar]

[R57] 57.Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature. 1996;379:349–53. doi: 10.1038/379349a0. [DOI] [PubMed] [Google Scholar]

[R58] 58.Scorrano L, Oakes SA, Opferman TJ, Cheng EH, Sorcinelli MD, Pozzan T, et al. Bax and Bak regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science. 2003;300:135–9. doi: 10.1126/science.1081208. [DOI] [PubMed] [Google Scholar]

[R59] 59.Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature. 1999;381:335–41. doi: 10.1038/381335a0. [DOI] [PubMed] [Google Scholar]

[R60] 60.Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, et al. Inhibition of bax channel-forming activity by bcl-2. Science. 1997;277:370–2. doi: 10.1126/science.277.5324.370. [DOI] [PubMed] [Google Scholar]

[R61] 61.Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2:183–92. doi: 10.1016/s1535-6108(02)00127-7. [DOI] [PubMed] [Google Scholar]

[R62] 62.Wei MC, Zong W-X, Cheng EH-Y, Lindsten T, Panoutsakopoulou V, Ross AJ, et al. Proapoptotic Bax and Bak: a requisite gateway to mitochondrial dysfunction and death. Science. 2001;292:727–30. doi: 10.1126/science.1059108. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R63] 63.Shimizu S, Ide T, Yanagida T, Tsujimoto Y. Electrophysiological study of a novel large pore formed by Bax and the voltage-dependent anion channel that is permeable to cytochrome c. J Biol Chem. 2000;275:12321–5. doi: 10.1074/jbc.275.16.12321. [DOI] [PubMed] [Google Scholar]

[R64] 64.Chowdhury I, Tharakan B, Bhat GH. Caspases—an update. Comp Biochem Physiol. 2008;51:10–27. doi: 10.1016/j.cbpb.2008.05.010. [DOI] [PubMed] [Google Scholar]

[R65] 65.Mancini M, Nicholson DW, Roy S, Thornberry NA, Peterson EP, Casciola-Rosen LA, et al. The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. J Cell Biol. 1998;140:1485–95. doi: 10.1083/jcb.140.6.1485. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R66] 66.Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraus QL, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA. 1999;96:5752–7. doi: 10.1073/pnas.96.10.5752. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R67] 67.Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997;89:175–84. doi: 10.1016/s0092-8674(00)80197-x. [DOI] [PubMed] [Google Scholar]

[R68] 68.Li H, Zhu H, Xu C-J, Yuan J. Cleavage of Bid by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94:491–501. doi: 10.1016/s0092-8674(00)81590-1. [DOI] [PubMed] [Google Scholar]

[R69] 69.Robertson JD, Enoksson M, Suomela M, Zhivotovsky B, Orrenius S. Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis. J Biol Chem. 2002;277:29803–9. doi: 10.1074/jbc.M204185200. [DOI] [PubMed] [Google Scholar]

[R70] 70.LaCasse EC, Baird S, Korneluk RG, MacKenzie AE. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 1998;17:3247–59. doi: 10.1038/sj.onc.1202569. [DOI] [PubMed] [Google Scholar]

[R71] 71.Holcik M. The IAP proteins. Trends Genet. 2002;18:537–8. doi: 10.1016/s0168-9525(02)02743-9. [DOI] [PubMed] [Google Scholar]

[R72] 72.Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 1998;17:2215–23. doi: 10.1093/emboj/17.8.2215. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R73] 73.Hao Y, Sekine K, Kawabata A, Nakamura H, Ishioka T, Ohata H, et al. Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function. Nat Cell Biol. 2004;6:849–60. doi: 10.1038/ncb1159. [DOI] [PubMed] [Google Scholar]

[R74] 74.Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42. doi: 10.1016/s0092-8674(00)00008-8. [DOI] [PubMed] [Google Scholar]

[R75] 75.Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000;102:43–53. doi: 10.1016/s0092-8674(00)00009-x. [DOI] [PubMed] [Google Scholar]

[R76] 76.Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell. 2001;8:613–21. doi: 10.1016/s1097-2765(01)00341-0. [DOI] [PubMed] [Google Scholar]

[R77] 77.Bogaerts V, Nuytemans K, Reumers J, Pals R, Engelborghs S, Pickut B, et al. Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson's disease. Hum Mutat. 2008;29:832–40. doi: 10.1002/humu.20713. [DOI] [PubMed] [Google Scholar]

[R78] 78.Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397:441–6. doi: 10.1038/17135. [DOI] [PubMed] [Google Scholar]

[R79] 79.Mate MJ, Ortiz-Lombardia M, Boitel B, Haouz A, Tello D, Susin SA, et al. The crystal structure of the mouse apoptosis-inducing factor AIF. Nat Struct Biol. 2002;9:442–6. doi: 10.1038/nsb793. [DOI] [PubMed] [Google Scholar]

[R80] 80.Trump BF, Berezesky IK. The role of altered [Ca2+]i regulation in apoptosis, oncosis, and necrosis. Biochim Biophys Acta. 1996;1313:173–8. doi: 10.1016/0167-4889(96)00086-9. [DOI] [PubMed] [Google Scholar]

[R81] 81.Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995;146:3–15. [PMC free article] [PubMed] [Google Scholar]

[R82] 82.Trump BJ, Goldblatt PJ, Stowell RE. Studies on necrosis of mouse liver in vitro. Ultrastructural alterations in the mitochondria of hepatic parenchymal cells. Lab Invest. 1964;14:343–71. [PubMed] [Google Scholar]

[R83] 83.Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell culture. Proc Natl Acad Sci USA. 1995;92:7162–6. doi: 10.1073/pnas.92.16.7162. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R84] 84.Leist M, Single B, Castoldi AF, Kuhnles S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med. 1997;185:1481–6. doi: 10.1084/jem.185.8.1481. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R85] 85.Golden WC, Brambrink AM, Traystman RJ, Martin LJ. Failure to sustain recovery of Na, K ATPase function is a possible mechanism for striatal neurodegeneration in hypoxic-ischemic newborn piglets. Mol Brain Res. 2001;88:94–102. doi: 10.1016/s0169-328x(01)00032-8. [DOI] [PubMed] [Google Scholar]

[R86] 86.Castro J, Ruminot I, Porras OH, Flores CM, Hermosilla T, Verdugo E, et al. ATP steal between cation pumps: a mechanism linking Na+ influx to the onset or necrotic Ca2+ overload. Cell Death Differ. 2006;13:1675–85. doi: 10.1038/sj.cdd.4401852. [DOI] [PubMed] [Google Scholar]

[R87] 87.Proskuryakov SY, Konoplyannikov AG, Gabai VL. Necrosis: a specific form of programmed cell death. Exp Cell Res. 2003;283:1–16. doi: 10.1016/s0014-4827(02)00027-7. [DOI] [PubMed] [Google Scholar]

[R88] 88.Kim Y-S, Morgan MJ, Choksi S, Lu Z-G. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell. 2007;26:675–87. doi: 10.1016/j.molcel.2007.04.021. [DOI] [PubMed] [Google Scholar]

[R89] 89.Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, et al. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008;135:1311–23. doi: 10.1016/j.cell.2008.10.044. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R90] 90.Baines CP, Kaiser RA, Purcell NH, Blair HS, Osinska H, Hambleton MA, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005;434:658–62. doi: 10.1038/nature03434. [DOI] [PubMed] [Google Scholar]

[R91] 91.Ha HC, Snyder SH. Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis. 2000;7:225–39. doi: 10.1006/nbdi.2000.0324. [DOI] [PubMed] [Google Scholar]

[R92] 92.Zoratti M, Szabo I. The mitochondrial permeability transition. Biochem Biophys Acta. 1995;1241:139–76. doi: 10.1016/0304-4157(95)00003-a. [DOI] [PubMed] [Google Scholar]

[R93] 93.Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999;341:233–49. [PMC free article] [PubMed] [Google Scholar]

[R94] 94.van Gurp M, Festjens N, van Loo G, Saelens X, Vandenabeele P. Mitochondrial intermembrane proteins in cell death. Biochem Biophys Res Commun. 2003;304:487–97. doi: 10.1016/s0006-291x(03)00621-1. [DOI] [PubMed] [Google Scholar]

[R95] 95.Leung AWC, Halestrap AP. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta. 2008;1777:946–52. doi: 10.1016/j.bbabio.2008.03.009. [DOI] [PubMed] [Google Scholar]

[R96] 96.Shoshan-Barmatz V, Israelson A, Brdiczka D, Sheu SS. The voltage-dependent anion channel (VDAC): function in intracellular signaling, cell life and cell death. Curr Pharm Des. 2006;12:2249–70. doi: 10.2174/138161206777585111. [DOI] [PubMed] [Google Scholar]

[R97] 97.Rostovtseva TK, Tan W, Colombini M. On the role of VDAC in apoptosis: fact and fiction. J Bioenerg Biomembr. 2005;37:129–42. doi: 10.1007/s10863-005-6566-8. [DOI] [PubMed] [Google Scholar]

[R98] 98.Tan W, Colombini M. VDAC closure increases calcium ion flux. Biochim Biophys Acta. 2007;1768:2510–5. doi: 10.1016/j.bbamem.2007.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R99] 99.Tikunov A, Johnson CB, Pediaditakis P, Markevich N, MacDonald JM, Lemasters JJ, et al. Closure of VDAC causes oxidative stress and accelerates the Ca2+-induced mitochondrial permeability transition in rat liver mitochondria. Arch Biochem Biophys. 2010;495:174–81. doi: 10.1016/j.abb.2010.01.008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R100] 100.Granville DJ, Gottlieb RA. The mitochondrial voltage-dependent anion channel (VDAC) as a therapeutic target for initiating cell death. Curr Med Chem. 2003;10:1527–33. doi: 10.2174/0929867033457214. [DOI] [PubMed] [Google Scholar]

[R101] 101.Huizing M, Ruitenbeek W, van den Heuvel LP, Dolce V, Iacobazzi V, Smeitink JAM, et al. Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders. J Bioenerg Biomembr. 1998;30:277–84. doi: 10.1023/a:1020501021222. [DOI] [PubMed] [Google Scholar]

[R102] 102.Wu S, Sampson MJ, Decker WK, Craigen WJ. Each mammalian mitochondrial outer membrane porin protein is dispensable: effects on cellular respiration. Biochem Biophys Acta. 1999;1452:68–78. doi: 10.1016/s0167-4889(99)00120-2. [DOI] [PubMed] [Google Scholar]

[R103] 103.Anflous K, Armstrong DD, Craigen WJ. Altered sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice. J Biol Chem. 2001;276:1954–60. doi: 10.1074/jbc.M006587200. [DOI] [PubMed] [Google Scholar]

[R104] 104.Sampson MJ, Decker WK, Beaudet AL, Ruitenbeek W, Armstrong D, Hicks MJ, et al. Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J Biol Chem. 2001;276:39206–12. doi: 10.1074/jbc.M104724200. [DOI] [PubMed] [Google Scholar]

[R105] 105.Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsemeyer SJ. VDAC2 inhibits Bak activation and mitochondrial apoptosis. Science. 2003;301:513–7. doi: 10.1126/science.1083995. [DOI] [PubMed] [Google Scholar]

[R106] 106.Chandra D, Choy G, Daniel PT, Tang DG. Bax-dependent regulation of Bak by voltage-dependent anion channel 2. J Biol Chem. 2005;280:19051–61. doi: 10.1074/jbc.M501391200. [DOI] [PubMed] [Google Scholar]

[R107] 107.Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol. 2007;9:550–5. doi: 10.1038/ncb1575. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R108] 108.Karachitos A, Galganska H, Wojtkowska M, Budzinska M, Stobienia O, Bartosz G, et al. Cu, Zn-superoxide dismutase is necessary for proper function of VDAC in Saccharomyces cerevisiae cells. FEBS Lett. 2009;583:449–55. doi: 10.1016/j.febslet.2008.12.045. [DOI] [PubMed] [Google Scholar]

[R109] 109.Halestrap AP, Brenner C. The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death. Curr Med Chem. 2003;10:1507–25. doi: 10.2174/0929867033457278. [DOI] [PubMed] [Google Scholar]

[R110] 110.Graham BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR, Wallace DC. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat Genet. 1997;16:226–34. doi: 10.1038/ng0797-226. [DOI] [PubMed] [Google Scholar]

[R111] 111.Stepien G, Torroni A, Chung AB, Hodge JA, Wallace DC. Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during muscle cell differentiation. J Biol Chem. 1992;267:14592–7. [PubMed] [Google Scholar]

[R112] 112.Vyssokikh MY, Katz A, Rueck A, Wuensch C, Dorner A, Zorov DB, et al. Adenine nucleotide translocator isoforms 1 and 2 are differently distributed in the mitochondrial inner membrane and have distinct affinities to cyclophilin D. Biochem J. 2001;358:349–58. doi: 10.1042/0264-6021:3580349. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R113] 113.Kikoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature. 2004;427:461–5. doi: 10.1038/nature02229. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R114] 114.Machida K, Hayashi Y, Osada H. A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome c release through a mitochondrial permeability transition-independent mechanisms. J Biol Chem. 2002;277:31243–8. doi: 10.1074/jbc.M204564200. [DOI] [PubMed] [Google Scholar]

[R115] 115.Woodfield K, Rück A, Brdiczka D, Halestrap AP. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J. 1998;336:287–90. doi: 10.1042/bj3360287. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R116] 116.Johnson N, Khan A, Virji S, Ward JM, Crompton M. Import and processing of heart mitochondrial cyclophilin D. Eur J Biochem. 1999;263:353–9. doi: 10.1046/j.1432-1327.1999.00490.x. [DOI] [PubMed] [Google Scholar]

[R117] 117.McEnery MW, Dawson TM, Verma A, Gurley D, Colombini M, Snyder SH. Mitochondrial voltage-dependent anion channel. J Biol Chem. 1993;268:23289–96. [PubMed] [Google Scholar]

[R118] 118.Shoshan-Barmatz V, Zalk R, Gincel D, Vardi N. Subcellular localization of VDAC in mitochondria and ER in the cerebellum. Biochem Biophys Acta. 2004;1657:105–14. doi: 10.1016/j.bbabio.2004.02.009. [DOI] [PubMed] [Google Scholar]

[R119] 119.Akanda N, Tofight R, Brask J, Tamm C, Elinder F, Ceccatelli S. Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells. Cell Cycle. 2008;7:3225–34. doi: 10.4161/cc.7.20.6831. [DOI] [PubMed] [Google Scholar]

[R120] 120.Yu WH, Wolfgang W, Forte M. Subcellular localization of human voltage-dependent anion channel isoforms. J Biol Chem. 1995;270:13998–4006. doi: 10.1074/jbc.270.23.13998. [DOI] [PubMed] [Google Scholar]

[R121] 121.Buck CR, Jurynec MJ, Upta DE, Law AKT, Bilger J, Wallace DC, et al. Increased adenine nucleotide translocator 1 in reactive astrocytes facilitates glutamate transport. Exp Neurol. 2003;181:149–58. doi: 10.1016/s0014-4886(03)00043-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R122] 122.Hazelton JL, Petrasheuskaya M, Fiskum G, Kristian T. Cyclophilin D is expressed predominantly in mitochondria of γ-aminobutyric acidergic interneurons. J Neurosci Res. 2009;87:1250–9. doi: 10.1002/jnr.21921. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R123] 123.Naga KK, Sullivan PG, Geddes JW. High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition. J Neurosci. 2007;27:7469–75. doi: 10.1523/JNEUROSCI.0646-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R124] 124.Martin LJ, Gertz B, Pan Y, Price AC, Molkentin JD, Chang Q. The mitochondrial permeability transition pore in motor neurons: involvement in the pathobiology of ALS mice. Exp Neurol. 2009;218:333–46. doi: 10.1016/j.expneurol.2009.02.015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R125] 125.Bose S, Freedman RB. Peptidyl prolyl cis-trans-isomerase activity associated with the lumen of the endoplasmic reticulum. Biochem J. 1994;300:865–70. doi: 10.1042/bj3000865. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R126] 126.Sullivan PG, Rabchevsky AG, Keller JN, Lovell M, Sodhi A, Hart RP, et al. Intrinsic differences in brain and spinal cord mitochondria: implications for therapeutic interventions. J Comp Neurol. 2004;474:524–34. doi: 10.1002/cne.20130. [DOI] [PubMed] [Google Scholar]

[R127] 127.Morota S, Hansson MJ, Ishii N, Kudo Y, Elmer E, Uchino H. Spinal cord mitochondria display lower calcium retention capacity compared with brain mitochondria without inherent differences in sensitivity to cyclophilin D inhibition. J Neurochem. 2007;103:2066–76. doi: 10.1111/j.1471-4159.2007.04912.x. [DOI] [PubMed] [Google Scholar]

[R128] 128.Collins TJ, Bootman MD. Mitochondria are morphologically heterogeneous within cells. J Exp Biol. 2003;206:1993–2000. doi: 10.1242/jeb.00244. [DOI] [PubMed] [Google Scholar]

[R129] 129.Jensen RE. Control of mitochondrial shape. Curr Opin Cell Biol. 2005;17:384–8. doi: 10.1016/j.ceb.2005.06.011. [DOI] [PubMed] [Google Scholar]

[R130] 130.Hamberger A, Blomstrand C, Lehninger AL. Comparative studies of mitochondria isolated from neuron-enriched and glia-enriched fractions of rabbit and beef brain. J Cell Biol. 1970;45:221–34. doi: 10.1083/jcb.45.2.221. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R131] 131.Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290:1717–21. doi: 10.1126/science.290.5497.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R132] 132.Tolkovsky AM, Xue L, Fletcher GC, Borutaite V. Mitochondrial disappearance from cells: a clue to the role of autophagy in programmed cell death and disease. Biochimie. 2002;84:233–40. doi: 10.1016/s0300-9084(02)01371-8. [DOI] [PubMed] [Google Scholar]

[R133] 133.Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 2004;23:2891–906. doi: 10.1038/sj.onc.1207521. [DOI] [PubMed] [Google Scholar]

[R134] 134.Ginsberg SD, Martin LJ. Ultrastructural analysis of the progression of neurodegeneration in the septum following fimbria-fornix transaction. Neuroscience. 1998;86:1259–72. doi: 10.1016/s0306-4522(98)00136-5. [DOI] [PubMed] [Google Scholar]

[R135] 135.Ginsberg SD, Portera-Cailliau C, Martin LJ. Fimbria-fronix transection and excitotoxicity produce similar neurodegeneration in the septum. Neuroscience. 1999;88:1059–1071. doi: 10.1016/s0306-4522(98)00288-7. [DOI] [PubMed] [Google Scholar]

[R136] 136.Martin LJ, Kaiser A, Price AC. Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis. J Neurobiol. 1999;40:185–201. [PubMed] [Google Scholar]

[R137] 137.Al-Abdulla NA, Martin LJ. Apoptosis of retrogradely degenerating neurons occurs in association with accumulation of perikaryal mitochondria and oxidative damage to the nucleus. Am J Pathol. 1998;153:447–56. doi: 10.1016/S0002-9440(10)65588-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R138] 138.Martin LJ. An approach to experimental synaptic pathology using green fluorescent protein-transgenic mice and gene knockout mice: excitotoxic vulnerability of interneurons and moto-neurons is associated with mitochondrial accumulation and mediated by the mitochondrial permeability transition pore. Toxicol Pathol. 2011;39(1):220–33. doi: 10.1177/0192623310389475. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R139] 139.Clarke PGH. Developmental cell death: morphological diversity and multiple mechanisms. Anat Embryol. 1990;181:195–213. doi: 10.1007/BF00174615. [DOI] [PubMed] [Google Scholar]

[R140] 140.Schweichel JU, Merker HJ. The morphology of various types of cell death in prenatal tissues. Teratology. 1973;7:253–66. doi: 10.1002/tera.1420070306. [DOI] [PubMed] [Google Scholar]

[R141] 141.Xue LZ, Fletcher GC, Tolkovsky AM. Autophagy is activated by apoptotic signaling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci. 1999;14:180–98. doi: 10.1006/mcne.1999.0780. [DOI] [PubMed] [Google Scholar]

[R142] 142.Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N. A novel protein complex linking the δ2 glutamate receptor and autophagy: implications for neurodegeneration in Lurcher mice. Neuron. 2002;35:921–33. doi: 10.1016/s0896-6273(02)00861-9. [DOI] [PubMed] [Google Scholar]

[R143] 143.Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;44:885–9. doi: 10.1038/nature04724. [DOI] [PubMed] [Google Scholar]

[R144] 144.Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;44:880–4. doi: 10.1038/nature04723. [DOI] [PubMed] [Google Scholar]

[R145] 145.Nakendra D, Tanaka A, Suen D-F, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803. doi: 10.1083/jcb.200809125. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R146] 146.Yuan J, Lipinski M, Degterev A. Diversity in the mechanisms of neuronal cell death. Neuron. 2003;40:401–13. doi: 10.1016/s0896-6273(03)00601-9. [DOI] [PubMed] [Google Scholar]

[R147] 147.Todde V, Veenhuis M, van der Klei IJ. Autophagy: principles and significance in health and disease. Biochim Biophys Acta. 2009;1792:3–13. doi: 10.1016/j.bbadis.2008.10.016. [DOI] [PubMed] [Google Scholar]

[R148] 148.Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ. 2001;8:569–81. doi: 10.1038/sj.cdd.4400852. [DOI] [PubMed] [Google Scholar]

[R149] 149.Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A. DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol. 2002;157:455–68. doi: 10.1083/jcb.200109094. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R150] 150.Liange XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586–96. doi: 10.1128/jvi.72.11.8586-8596.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R151] 151.Ogier-Denis E, Codogno P. Autophagy: a barrier or an adaptive response to cancer. Biochim Biophys Acta. 2003;1603:113–28. doi: 10.1016/s0304-419x(03)00004-0. [DOI] [PubMed] [Google Scholar]

[R152] 152.Varadi A, Johnson-Cadwell LI, Cirulli V, Yoon Y, Allan VJ, Rutter GA. Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1. J Cell Sci. 2004;117:4389–400. doi: 10.1242/jcs.01299. [DOI] [PubMed] [Google Scholar]

[R153] 153.Karbowski M, Lee Y-L, Gaume B, Jeong S-Y, Frank S, Nechushtan A, et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol. 2002;159:931–8. doi: 10.1083/jcb.200209124. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R154] 154.Davis AF, Clayton DA. In situ localization of mitochondrial DNA replication in intact mammalian cells. J Cell Biol. 1996;135:883–93. doi: 10.1083/jcb.135.4.883. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R155] 155.Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science. 2003;299:896–9. doi: 10.1126/science.1079368. [DOI] [PubMed] [Google Scholar]

[R156] 156.Katzman R. Education and the prevalence of dementia and Alzheimer's disease. Neurology. 1993;43:13–20. doi: 10.1212/wnl.43.1_part_1.13. [DOI] [PubMed] [Google Scholar]

[R157] 157.Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA. 1989;262:2551–6. [PubMed] [Google Scholar]

[R158] 158.McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services task force on Alzheimer's disease. Neurology. 1984;34:939–44. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]

[R159] 159.Olshansky SJ, Carnes BA, Cassel CK. The aging of the human species. Sci Am. 1993;268:46–52. doi: 10.1038/scientificamerican0493-46. [DOI] [PubMed] [Google Scholar]

[R160] 160.Minati L, Edginton T, Bruzzone MG, Giaccone G. Current concepts in Alzheimer's disease: a multidisciplinary review. Am J Alz Dis Other Dem. 2009;24:95–121. doi: 10.1177/1533317508328602. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R161] 161.Chartier-Harlin M-C, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature. 1991;353:844–6. doi: 10.1038/353844a0. [DOI] [PubMed] [Google Scholar]

[R162] 162.Tilley L, Morgan K, Kalsheker N. Genetic risk factors for Alzheimer's disease. J Clin Pathol Mol Pathol. 1998;51:293–304. doi: 10.1136/mp.51.6.293. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R163] 163.Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991;349:704–6. doi: 10.1038/349704a0. [DOI] [PubMed] [Google Scholar]

[R164] 164.Naruse S, Igarashi S, Kobayashi H, Aoki K, Inuzuka T, Kaneko K, et al. Mis-sense mutation Val->Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet. 1991;337:978–9. doi: 10.1016/0140-6736(91)91612-x. [DOI] [PubMed] [Google Scholar]

[R165] 165.Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, et al. Mutations of the presenilin 1 gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995;4:2373–7. doi: 10.1093/hmg/4.12.2373. [DOI] [PubMed] [Google Scholar]

[R166] 166.Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375:754–60. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar]

[R167] 167.Kalaria RN. Dementia comes of age in the developing world. Lancet. 2003;361:888–9. doi: 10.1016/S0140-6736(03)12783-3. [DOI] [PubMed] [Google Scholar]

[R168] 168.Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer's disease. Annu Rev Med. 1996;47:387–400. doi: 10.1146/annurev.med.47.1.387. [DOI] [PubMed] [Google Scholar]

[R169] 169.Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, DeLong MR. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215:1237–9. doi: 10.1126/science.7058341. [DOI] [PubMed] [Google Scholar]

[R170] 170.Gomez-Isla T, Price JL, McKeel DW, Jr., Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci. 1996;16:4491–500. doi: 10.1523/JNEUROSCI.16-14-04491.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R171] 171.Mouton PR, Martin LJ, Calhoun ME, Dal Forno G, Price DL. Cognitive decline strongly correlates with cortical atrophy in Alzheimer's disease. Neurobiol Aging. 1998;19:371–7. doi: 10.1016/s0197-4580(98)00080-3. [DOI] [PubMed] [Google Scholar]

[R172] 172.West MJ, Kawas CH, Martin LJ, Troncoso JC. The CA1 region of the human hippocampus is a hot spot in Alzheimer's disease. Annu NY Acad Sci. 2000;908:255–9. doi: 10.1111/j.1749-6632.2000.tb06652.x. [DOI] [PubMed] [Google Scholar]

[R173] 173.Pelvig DP, Pakkenberg H, Regeur L, Oster S, Pakkenberg B. Neocortical glial cell numbers in Alzheimer's disease. A stereological study. Dement Geriatr Cogn Disord. 2003;16:212–9. doi: 10.1159/000072805. [DOI] [PubMed] [Google Scholar]

[R174] 174.Troncoso JC, Cataldo AM, Nixon RA, Barnett JL, Lee MK, Checler F, et al. Neuropathology of preclinical and clinical late-onset Alzheimer's disease. Ann Neurol. 1998;43:673–6. doi: 10.1002/ana.410430519. [DOI] [PubMed] [Google Scholar]

[R175] 175.Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau is a major antigenic component of paired helical filaments in Alzheimer's disease. Proc Natl Acad Sci USA. 1986;83:4044–8. doi: 10.1073/pnas.83.11.4044. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R176] 176.Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6. doi: 10.1126/science.1072994. [DOI] [PubMed] [Google Scholar]

[R177] 177.Sze C-I, Bi H, Kleinschmidt-DeMasters BK, Filley CM, Martin LJ. N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer's disease. J Neurol Sci. 2001;182:151–9. doi: 10.1016/s0022-510x(00)00467-6. [DOI] [PubMed] [Google Scholar]

[R178] 178.Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat Neurosci. 2002;5:1039–42. doi: 10.1038/nn936. [DOI] [PubMed] [Google Scholar]

[R179] 179.Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxi-city. J Neurosci. 1993;12:376–89. doi: 10.1523/JNEUROSCI.12-02-00376.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R180] 180.Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008;14:45–53. doi: 10.1016/j.molmed.2007.12.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R181] 181.DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64. doi: 10.1002/ana.410270502. [DOI] [PubMed] [Google Scholar]

[R182] 182.Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80. doi: 10.1002/ana.410300410. [DOI] [PubMed] [Google Scholar]

[R183] 183.Martin LJ, Pardo CA, Cork LC, Price DL. Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am J Pathol. 1994;145:1358–81. [PMC free article] [PubMed] [Google Scholar]

[R184] 184.Sze C-I, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer's disease. J Neuropathol Exp Neurol. 1997;56:933–94. doi: 10.1097/00005072-199708000-00011. [DOI] [PubMed] [Google Scholar]

[R185] 185.Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298:789–91. doi: 10.1126/science.1074069. [DOI] [PubMed] [Google Scholar]

[R186] 186.Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science. 1989;245:417–20. doi: 10.1126/science.2474201. [DOI] [PubMed] [Google Scholar]

[R187] 187.Younkin SG. Evidence that Abeta 42 is the real culprit in Alzheimer's disease. Ann Neurol. 1995;37:287–8. doi: 10.1002/ana.410370303. [DOI] [PubMed] [Google Scholar]

[R188] 188.Fath T, Eidenmuller J, Brandt R. Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease. J Neurosci. 2002;22:9733–41. doi: 10.1523/JNEUROSCI.22-22-09733.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R189] 189.Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to β-amyloid-induced neurotoxicity. Proc Natl Acad Sci USA. 2002;99:6364–9. doi: 10.1073/pnas.092136199. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R190] 190.Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol. 2003;161:41–54. doi: 10.1083/jcb.200207030. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R191] 191.Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006;26:9057–68. doi: 10.1523/JNEUROSCI.1469-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R192] 192.Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006;15:1437–49. doi: 10.1093/hmg/ddl066. [DOI] [PubMed] [Google Scholar]

[R193] 193.Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease. Science. 2004;304:448–52. doi: 10.1126/science.1091230. [DOI] [PubMed] [Google Scholar]

[R194] 194.Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, et al. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med. 2008;14:1097–105. doi: 10.1038/nm.1868. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R195] 195.Duyckaerts C, Potier MC, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol. 2008;115:5–38. doi: 10.1007/s00401-007-0312-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R196] 196.Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, et al. Incidence of Parkinson's disease: variations by age, gender and race ethnicity. Am J Epidemol. 2003;157:1015–22. doi: 10.1093/aje/kwg068. [DOI] [PubMed] [Google Scholar]

[R197] 197.Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79:368–76. doi: 10.1136/jnnp.2007.131045. [DOI] [PubMed] [Google Scholar]

[R198] 198.Lowe J, Lennox G, Leigh PN. Disorders of movement and system degeneration. In: Graham DI, Lantos PL, editors. Greenfields neuropathology. Arnold; London: 1997. pp. 281–366. [Google Scholar]

[R199] 199.Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24:197–211. doi: 10.1016/s0197-4580(02)00065-9. [DOI] [PubMed] [Google Scholar]

[R200] 200.Martin LJ. Neurodegenerative disorders of the human brain and spinal cord. In: Ramachandran VS, editor. Encyclopedia of the human brain. Vol. 3. Elsevier Science; Amsterdam: 2002. pp. 441–63. [Google Scholar]

[R201] 201.Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001;2:492–501. doi: 10.1038/35081564. [DOI] [PubMed] [Google Scholar]

[R202] 202.Ascherio A, Chen H, Weisskopf MG, O'Reilly E, McCullough ML, Calle EE, et al. Pesticide exposure and risk for Parkinson's disease. Ann Neurol. 2006;60:197–203. doi: 10.1002/ana.20904. [DOI] [PubMed] [Google Scholar]

[R203] 203.Schapira AHV. Etiology of Parkinson's disease. Neurology. 2006;66(Suppl. 4):S10–23. doi: 10.1212/wnl.66.10_suppl_4.s10. [DOI] [PubMed] [Google Scholar]

[R204] 204.Shimohama S, Swada H, Kitamura Y, Taniguchi T. Disease model: Parkinson's disease. Trends Mol Med. 2003;9:360–5. doi: 10.1016/s1471-4914(03)00117-5. [DOI] [PubMed] [Google Scholar]

[R205] 205.Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science. 1997;276:2045–7. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]

[R206] 206.Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, et al. Alpha-synuclein locus triplication causes Parkinson's disease. Science. 2003;302:841. doi: 10.1126/science.1090278. [DOI] [PubMed] [Google Scholar]

[R207] 207.Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, et al. The ubiquitin pathway in Parkinson's disease. Nature. 1998;395:451–2. doi: 10.1038/26652. [DOI] [PubMed] [Google Scholar]

[R208] 208.Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299:256–9. doi: 10.1126/science.1077209. [DOI] [PubMed] [Google Scholar]

[R209] 209.Hatano Y, Li Y, Sato K, Asakawa S, Yamamura Y, Tomiyama H, et al. Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol. 2004;56:424–7. doi: 10.1002/ana.20251. [DOI] [PubMed] [Google Scholar]

[R210] 210.Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8. doi: 10.1038/33416. [DOI] [PubMed] [Google Scholar]

[R211] 211.Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert A, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004;304:1158–60. doi: 10.1126/science.1096284. [DOI] [PubMed] [Google Scholar]

[R212] 212.Paisán-Ruíz C, Jain S, Whitney Evans E, Gilks WP, Simón J, van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004;44:595–600. doi: 10.1016/j.neuron.2004.10.023. [DOI] [PubMed] [Google Scholar]

[R213] 213.Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–7. doi: 10.1016/j.neuron.2004.11.005. [DOI] [PubMed] [Google Scholar]

[R214] 214.Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38:1184–91. doi: 10.1038/ng1884. [DOI] [PubMed] [Google Scholar]

[R215] 215.Lesuisse C, Martin LJ. Long-term culture of mouse cortical neurons as a model for neuronal development, aging, and death. J Neurobiol. 2002;51:9–23. doi: 10.1002/neu.10037. [DOI] [PubMed] [Google Scholar]

[R216] 216.Maroteaux L, Campanelli JT, Scheller RH. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminals. J Neurosci. 1998;8:2804–15. doi: 10.1523/JNEUROSCI.08-08-02804.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R217] 217.Murphy DD, Rueter SM, Trojanowski JQ, Lee VMY. Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000;20:3214–20. doi: 10.1523/JNEUROSCI.20-09-03214.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R218] 218.Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, et al. Double knockout mice for α- and β-synucleins: effect on synaptic functions. Proc Natl Acad Sci USA. 2004;101:14966–71. doi: 10.1073/pnas.0406283101. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R219] 219.Gurevicine I, Gurevicius K, Tanila H. Role of α-synuclein in synaptic glutamate release. Neurobiol Dis. 2007;28:83–9. doi: 10.1016/j.nbd.2007.06.016. [DOI] [PubMed] [Google Scholar]

[R220] 220.Liu S, Fa M, Ninan I, Trinchese F, Dauer W, Aranico O. α-Synuclein involvement in hippocampal synaptic plasticity: role of NO, cGMP, cGK and CAMKII. Eur J Neurosci. 2007;25:3583–96. doi: 10.1111/j.1460-9568.2007.05569.x. [DOI] [PubMed] [Google Scholar]

[R221] 221.Fortin DL, Nemani VM, Voglmaier SM, Anthony MD, Ryan TA, Edwards RH. Neural activity control the synaptic accumulation of α-synuclein. J Neurosci. 2005;25:10913–21. doi: 10.1523/JNEUROSCI.2922-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R222] 222.Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudholf TC. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell. 2005;123:383–96. doi: 10.1016/j.cell.2005.09.028. [DOI] [PubMed] [Google Scholar]

[R223] 223.Gallardo G, Schluter OM, Sudhof TC. A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides. Nat Neurosci. 2008;11:301–8. doi: 10.1038/nn2058. [DOI] [PubMed] [Google Scholar]

[R224] 224.Serpell LC, Berriman J, Jakes M, Goedert M, Crowther RA. Fiber diffraction of synthetic alpha synuclein filaments shows amyloid-like cross-beta conformation. Proc Natl Acad Sci USA. 2000;97:4897–902. doi: 10.1073/pnas.97.9.4897. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R225] 225.Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT., Jr. Acceleration of oligomerization, not fibrilization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA. 2000;97:571–6. doi: 10.1073/pnas.97.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R226] 226.Caughey B, Lansbury PT. Protofibrils, pores, fibril, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267–98. doi: 10.1146/annurev.neuro.26.010302.081142. [DOI] [PubMed] [Google Scholar]

[R227] 227.Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, et al. Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol. 2000;157:401–10. doi: 10.1016/s0002-9440(10)64553-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R228] 228.Junn E, Mouradian MM. Human α-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett. 2002;320:146–50. doi: 10.1016/s0304-3940(02)00016-2. [DOI] [PubMed] [Google Scholar]

[R229] 229.Tabrizi SJ, Orth M, Wilkinson JM, Taanman JW, Warner TT, Cooper JM, et al. Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity. Hum Mol Genet. 2000;9:2683–9. doi: 10.1093/hmg/9.18.2683. [DOI] [PubMed] [Google Scholar]

[R230] 230.Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee WM-Y. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron. 2002;34:521–33. doi: 10.1016/s0896-6273(02)00682-7. [DOI] [PubMed] [Google Scholar]

[R231] 231.Giasson BI, Duda JE, Murray IVJ, Chen Q, Souza JM, Hurtig HI, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000;290:985–9. doi: 10.1126/science.290.5493.985. [DOI] [PubMed] [Google Scholar]

[R232] 232.Ischiropoulos H. Oxidative modification of alpha-synuclein. Annu NY Acad Sci. 2003;991:93–100. doi: 10.1111/j.1749-6632.2003.tb07466.x. [DOI] [PubMed] [Google Scholar]

[R233] 233.Wilkinson KD, Lee KM, Deshpande S, Duerken-Hughes P, Boss JM, Pohl J. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl terminal hydrolase. Science. 1989;246:670–3. doi: 10.1126/science.2530630. [DOI] [PubMed] [Google Scholar]

[R234] 234.Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–79. doi: 10.1146/annurev.biochem.67.1.425. [DOI] [PubMed] [Google Scholar]

[R235] 235.Lansbury PT, Jr., Brice A. Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr Opin Cell Biol. 2002;14:653–60. doi: 10.1016/s0955-0674(02)00377-0. [DOI] [PubMed] [Google Scholar]

[R236] 236.McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shahidharan P, Jennert P, et al. Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem. 2002;81:301–6. doi: 10.1046/j.1471-4159.2002.00821.x. [DOI] [PubMed] [Google Scholar]

[R237] 237.Imai Y, Takahashi R. How do Parkin mutations result in neurodegeneration? Curr Opin Neurobiol. 2004;14:384–9. doi: 10.1016/j.conb.2004.04.002. [DOI] [PubMed] [Google Scholar]

[R238] 238.Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, et al. Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene. Biochem Biophys Res Commun. 1998;249:754–8. doi: 10.1006/bbrc.1998.9134. [DOI] [PubMed] [Google Scholar]

[R239] 239.Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci USA. 2005;102:5703–8. doi: 10.1073/pnas.0500617102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R240] 240.Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet. 2005;14:3477–92. doi: 10.1093/hmg/ddi377. [DOI] [PubMed] [Google Scholar]

[R241] 241.Unoki M, Nakamura Y. Growth-suppressive effects of BPOZ and RGR2, two genes involved in the PTEN signaling pathway. Oncogene. 2001;20:4457–65. doi: 10.1038/sj.onc.1204608. [DOI] [PubMed] [Google Scholar]

[R242] 242.Taymans J-M, Van den Haute C, Baekelandt V. Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem. 2006;98:951–61. doi: 10.1111/j.1471-4159.2006.03919.x. [DOI] [PubMed] [Google Scholar]

[R243] 243.Weihofen A, Thomas KJ, Ostazewski BL, Cooksen MR, Selkoe DJ. Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry. 2009;48:2045–52. doi: 10.1021/bi8019178. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R244] 244.Deng H, Jankovic J, Guo Y, Xie W, Le W. Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun. 2005;337:1133–8. doi: 10.1016/j.bbrc.2005.09.178. [DOI] [PubMed] [Google Scholar]

[R245] 245.Marongiu R, Spencer B, Crews L, Adame A, Patrick C, Trejo M, et al. Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. J Neurochem. 2009;108:1561–74. doi: 10.1111/j.1471-4159.2009.05932.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R246] 246.Wilson MA, Collins JL, Hod Y, Ringe D, Petsko GA. The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. Proc Natl Acad Sci USA. 2003;100:9256–61. doi: 10.1073/pnas.1133288100. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R247] 247.Shang H, Lang D, Jean-Marc B, Kaelin-Lang A. Localization of DJ-1 mRNA in the mouse brain. Neurosci Lett. 2004;367:273–7. doi: 10.1016/j.neulet.2004.06.002. [DOI] [PubMed] [Google Scholar]

[R248] 248.Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA. 2004;101:9103–8. doi: 10.1073/pnas.0402959101. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R249] 249.Miller DW, Ahmad R, Hague S, Baptista MJ, Canet-Aviles R, McLendon C, et al. L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system. J Biol Chem. 2003;278:36588–95. doi: 10.1074/jbc.M304272200. [DOI] [PubMed] [Google Scholar]

[R250] 250.Takahashi-Niki K, Niki T, Taira T, Iguchi-Ariga SM, Ariga H. Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients. Biochem Biophys Res Commun. 2004;320:389–97. doi: 10.1016/j.bbrc.2004.05.187. [DOI] [PubMed] [Google Scholar]

[R251] 251.Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L. LRRK2 expression linked to dopamine-innervated areas. Ann Neurol. 2006;59:714–9. doi: 10.1002/ana.20808. [DOI] [PubMed] [Google Scholar]

[R252] 252.Melrose H, Lincoln S, Tyndall G, Dickson D, Farrer M. Anatomical localization of leucine-rich repeat kinase 2 mouse brain. Neuroscience. 2006;139:791–4. doi: 10.1016/j.neuroscience.2006.01.017. [DOI] [PubMed] [Google Scholar]

[R253] 253.Iaccarino C, Crosio C, Vitale C, Sanna G, Carri MT, Barone P. Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet. 2007;16:1319–26. doi: 10.1093/hmg/ddm080. [DOI] [PubMed] [Google Scholar]

[R254] 254.Ho CC-Y, Rideout HJ, Ribe E, Troy CM, Dauer WT. The Parkinson's disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci. 2009;29:1011–6. doi: 10.1523/JNEUROSCI.5175-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R255] 255.Goldberg MS, Fleming SM, Palacino JJ, Capedam C, Lam HA, Bhatnagar A, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 2003;278:43628–35. doi: 10.1074/jbc.M308947200. [DOI] [PubMed] [Google Scholar]

[R256] 256.Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA. 2005;102:2174–9. doi: 10.1073/pnas.0409598102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R257] 257.Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004;279:18614–22. doi: 10.1074/jbc.M401135200. [DOI] [PubMed] [Google Scholar]

[R258] 258.Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Ding Y, et al. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem. 2005;280:21418–26. doi: 10.1074/jbc.M413955200. [DOI] [PubMed] [Google Scholar]

[R259] 259.Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada Y, Costa C, et al. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial parkinsonism-linked gene DJ-1. Neuron. 2005;45:489–96. doi: 10.1016/j.neuron.2005.01.041. [DOI] [PubMed] [Google Scholar]

[R260] 260.Lu X-H, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, et al. Bacterial artificial chromosome transgenic mice expressing a truncated mutant Parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of protein-ase K-resistant α-synuclein. J Neurosci. 2009;29:1962–76. doi: 10.1523/JNEUROSCI.5351-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R261] 261.Gispert S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, et al. Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence or aggregate formation. Mol Cell Neurosci. 2003;24:419–29. doi: 10.1016/s1044-7431(03)00198-2. [DOI] [PubMed] [Google Scholar]

[R262] 262.Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Schindzielorz A, et al. Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha-synuclein in human and transgenic mouse brain. J Neurosci. 2000;20:6365–73. doi: 10.1523/JNEUROSCI.20-17-06365.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R263] 263.Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, et al. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic!mice. Proc Natl Acad Sci USA. 2002;99:8968–73. doi: 10.1073/pnas.132197599. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R264] 264.Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science. 2000;287:1265–9. doi: 10.1126/science.287.5456.1265. [DOI] [PubMed] [Google Scholar]

[R265] 265.Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuetzer C, Gainetdinov RR, Caron MG, et al. Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol. 2002;175:35–48. doi: 10.1006/exnr.2002.7882. [DOI] [PubMed] [Google Scholar]

[R266] 266.van der Putten H, Wiederhold K-H, Probst A, Barbieri S, Mistl C, Danner S, et al. Neuropathology in mice expressing human α-synuclein. J Neurosci. 2000;20:6021–9. doi: 10.1523/JNEUROSCI.20-16-06021.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R267] 267.Wakamatsu M, Ishii A, Iwata S, Sakagami J, Ukai Y, Ono M, et al. Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein. Neurobiol Aging. 2008;29:547–85. doi: 10.1016/j.neurobiolaging.2006.11.017. [DOI] [PubMed] [Google Scholar]

[R268] 268.Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, et al. Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci. 2006;26:41–50. doi: 10.1523/JNEUROSCI.4308-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R269] 269.Lieberman AR. The axon reaction: a review of the principal features of perikaryal responses to axon injury. Int Rev Neurobiol. 1971;14:49–124. doi: 10.1016/s0074-7742(08)60183-x. [DOI] [PubMed] [Google Scholar]

[R270] 270.Poon HF, Frasier M, Shreve N, Calabrese V, Wolozin B, Butterfield DA. Mitochondrial associated metabolic proteins are selectively oxidized in A30P α-synuclein transgenic mice—a model of familial Parkinson's disease. Neurobiol Dis. 2005;18:492–8. doi: 10.1016/j.nbd.2004.12.009. [DOI] [PubMed] [Google Scholar]

[R271] 271.Turnbull S, Tabner BJ, El-Agnaf OM, Moore S, Davies Y, Allsop D. Alpha-synuclein implicated in Parkinson's disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med. 2001;30:1163–70. doi: 10.1016/s0891-5849(01)00513-5. [DOI] [PubMed] [Google Scholar]

[R272] 272.Paxinou E, Chen Q, Weisse M, Giasson BI, Norris EH, Rueter SM, et al. Induction of alpha-synuclein aggregation by intracellular nitrative insult. J Neurosci. 2001;21:8053–61. doi: 10.1523/JNEUROSCI.21-20-08053.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R273] 273.Souza JM, Giasson BI, Chen Q, Lee VM-Y, Ischiropoulos H. Dityrosine cross-linking promotes formation of stable α-synuclein polymers. J Biol Chem. 2000;265:18344–9. doi: 10.1074/jbc.M000206200. [DOI] [PubMed] [Google Scholar]

[R274] 274.Martin LJ, Liu Z, Chen K, Price AC, Pan Y, Swaby JA, et al. Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J Comp Neurol. 2007;500:20–46. doi: 10.1002/cne.21160. [DOI] [PubMed] [Google Scholar]

[R275] 275.Chen K, Northington FJ, Martin LJ. Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice. Brain Struct Funct. 2010;214:219–34. doi: 10.1007/s00429-009-0226-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R276] 276.Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001;344:1688–700. doi: 10.1056/NEJM200105313442207. [DOI] [PubMed] [Google Scholar]

[R277] 277.Sathasivam S, Ince PG, Shaw PJ. Apoptosis in amyotrophic lateral sclerosis: a review of the evidence. Neuropathol Appl Neurobiol. 2001;27:257–74. doi: 10.1046/j.0305-1846.2001.00332.x. [DOI] [PubMed] [Google Scholar]

[R278] 278.Stephens B, Guiloff RJ, Navarrete R, Newman P, Nikhar N, Lewis P. Widespread loss of neuronal populations in spinal ventral horn in sporadic motor neuron disease. A morphometric study. J Neurol Sci. 2006;244:41–58. doi: 10.1016/j.jns.2005.12.003. [DOI] [PubMed] [Google Scholar]

[R279] 279.Maekawa S, Al-Sarraj S, Kibble M, Landau S, Parnavelas J, Cotter D, et al. Cortical selective vulnerability in motor neurons disease: a morphometric study. Brain. 2004;127:1237–51. doi: 10.1093/brain/awh132. [DOI] [PubMed] [Google Scholar]

[R280] 280.Zoccolella S, Santamato A, Lamberti P. Current and emerging treatments for amyotrophic lateral sclerosis. Neuropsychiatr Dis Treat. 2009;5:577–95. doi: 10.2147/ndt.s7788. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R281] 281.Kabashi E, Valdmains PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40:572–4. doi: 10.1038/ng.132. [DOI] [PubMed] [Google Scholar]

[R282] 282.Deng H-X, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung W-Y, et al. Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science. 1993;261:1047–51. doi: 10.1126/science.8351519. [DOI] [PubMed] [Google Scholar]

[R283] 283.Vance C, Rogelj B, Hortobagyi T, de Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323:1208–11. doi: 10.1126/science.1165942. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R284] 284.Schymick JC, Talbot K, Traynor GJ. Genetics of amyotrophic lateral sclerosis. Hum Mol Genet. 2007;16:R233–42. doi: 10.1093/hmg/ddm215. [DOI] [PubMed] [Google Scholar]

[R285] 285.Chow CY, Lander JE, Bergren SK, Sapp PC, Grant AE, Jones JM, et al. Deleterious variants of FIG4, a phosphoinositade phosphatase, in patients with ALS. Am J Hum Genet. 2009;84:85–8. doi: 10.1016/j.ajhg.2008.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R286] 286.Sasaki S, Iwata M. Ultrastructural changes of synapses of Betz cell in patients with amyotrophic lateral sclerosis. Neurosci Lett. 1999;268:29–32. doi: 10.1016/s0304-3940(99)00374-2. [DOI] [PubMed] [Google Scholar]

[R287] 287.Menzies FM, Ince PG, Shaw PJ. Mitochondrial involvement in amyotrophic lateral sclerosis. Neurochem Int. 2002;40:543–51. doi: 10.1016/s0197-0186(01)00125-5. [DOI] [PubMed] [Google Scholar]

[R288] 288.Comi GP, Bordoni A, Salani S, Franeschina L, Sciacco M, Prelle A, et al. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann Neurol. 1998;43:110–6. doi: 10.1002/ana.410430119. [DOI] [PubMed] [Google Scholar]

[R289] 289.Borthwick GM, Taylo RW, Walls TJ, Tonska K, Taylor GA, Shaw PJ, et al. Motor neuron disease in a patient with a mitochondrial tRNAIle mutation. Ann Neurol. 2006;59:570–4. doi: 10.1002/ana.20758. [DOI] [PubMed] [Google Scholar]

[R290] 290.Mawrin C, Kirches E, Krause G, Wiedemann FR, Vorwerk CK, Bogerts B, et al. Single-cell analysis of mtDNA levels in sporadic amyotrophic lateral sclerosis. Neuroreport. 2004;15:939–43. doi: 10.1097/00001756-200404290-00002. [DOI] [PubMed] [Google Scholar]

[R291] 291.Bender A, Krishnan KJ, Morris CM, Taylor GA, Reve AK, Perry RP, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson's disease. Nat Genet. 2006;38:515–7. doi: 10.1038/ng1769. [DOI] [PubMed] [Google Scholar]

[R292] 292.Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet. 2006;38:518–20. doi: 10.1038/ng1778. [DOI] [PubMed] [Google Scholar]

[R293] 293.Babcock D, Hille B. Mitochondrial oversight of cellular Ca2+ signaling. Curr Opin Neurobiol. 1998;8:398–404. doi: 10.1016/s0959-4388(98)80067-6. [DOI] [PubMed] [Google Scholar]

[R294] 294.Siklos L, Engelhardt J, Harat Y, Smith RG, Joo F, Appel SH. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol. 1996;39:203–16. doi: 10.1002/ana.410390210. [DOI] [PubMed] [Google Scholar]

[R295] 295.Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med. 1992;326:1464–8. doi: 10.1056/NEJM199205283262204. [DOI] [PubMed] [Google Scholar]

[R296] 296.Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995;38:73–84. doi: 10.1002/ana.410380114. [DOI] [PubMed] [Google Scholar]

[R297] 297.Heath PR, Tomkins J, Ince PG, Shaw PJ. Quantitative assessment of AMPA receptor mRNA in human spinal motor neurons isolated by laser capture microdissection. Neuroreport. 2002;13:1753–7. doi: 10.1097/00001756-200210070-00012. [DOI] [PubMed] [Google Scholar]

[R298] 298.Kwak S, Kawahara Y. Deficient RNA editing of GluR2 and neuronal death in amyotrophic lateral sclerosis. J Mol Med. 2005;83:110–20. doi: 10.1007/s00109-004-0599-z. [DOI] [PubMed] [Google Scholar]

[R299] 299.Chang DTW, Reynolds IJ. Mitochondrial trafficking and morphology in healthy and injured neurons. Prog Brain Res. 2006;80:241–68. doi: 10.1016/j.pneurobio.2006.09.003. [DOI] [PubMed] [Google Scholar]

[R300] 300.Hansson MJ, Mansson R, Morota S, Uchino H, Kallur T, Sumi T, et al. Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition. Free Radic Biol Med. 2008;45:284–94. doi: 10.1016/j.freeradbiomed.2008.04.021. [DOI] [PubMed] [Google Scholar]

[R301] 301.Bergmann F, Keller BU. Impact of mitochondrial inhibition on excitability and cytosolic Ca2+ levels in brainstem motoneurones. J Physiol. 2004;555:45–59. doi: 10.1113/jphysiol.2003.053900. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R302] 302.Beal MF. Oxidatively modified protein in aging and disease. Free Radic Biol Med. 2002;32:797–803. doi: 10.1016/s0891-5849(02)00780-3. [DOI] [PubMed] [Google Scholar]

[R303] 303.Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997;69:2064–74. doi: 10.1046/j.1471-4159.1997.69052064.x. [DOI] [PubMed] [Google Scholar]

[R304] 304.Abe K, Pan L-H, Watanabe M, Kato T, Itoyama Y. Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis. Neurosci Lett. 1995;199:152–4. doi: 10.1016/0304-3940(95)12039-7. [DOI] [PubMed] [Google Scholar]

[R305] 305.Beal MF, Ferrante RJ, Browne SE, Matthews RT, Kowall NW, Brown RH., Jr. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol. 1997;42:644–54. doi: 10.1002/ana.410420416. [DOI] [PubMed] [Google Scholar]

[R306] 306.Sasaki S, Warita H, Abe K, Iwata M. Inducible nitric oxide synthase (iNOS) and nitrotyrosine immunoreactivity in the spinal cords of transgenic mice with mutant SOD1 gene. J Neuropathol Exp Neurol. 2001;60:839–46. doi: 10.1093/jnen/60.9.839. [DOI] [PubMed] [Google Scholar]

[R307] 307.Browne SE, Bowling AC, Baik MJ, Gurney M, Brown RH, Jr., Beal MF. Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. J Neurochem. 1998;71:281–7. doi: 10.1046/j.1471-4159.1998.71010281.x. [DOI] [PubMed] [Google Scholar]

[R308] 308.Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol. 1999;46:787–90. doi: 10.1002/1531-8249(199911)46:5<787::aid-ana17>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]

[R309] 309.Vielhaber S, Kunz D, Winkler K, Wiedemann FR, Kirches E, Feistner H, et al. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain. 2000;123:1339–48. doi: 10.1093/brain/123.7.1339. [DOI] [PubMed] [Google Scholar]

[R310] 310.Soraru G, Vergani L, Fedrizzi L, D'Ascenzo C, Polo A, Bernazzi B, et al. Activities of mitochondrial complexes correlate with nNOS amount in muscle from ALS patients. Neuropathol Appl Neurobiol. 2007;33:204–11. doi: 10.1111/j.1365-2990.2006.00791.x. [DOI] [PubMed] [Google Scholar]

[R311] 311.Echaniz-Laguna A, Zoll J, Ponsot E, N'Guessan B, Tranchant C, Loeffler J-P, et al. Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: a temporal study in man. Exp Neurol. 2006;198:25–30. doi: 10.1016/j.expneurol.2005.07.020. [DOI] [PubMed] [Google Scholar]

[R312] 312.Martin LJ. Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol. 1999;58:459–71. doi: 10.1097/00005072-199905000-00005. [DOI] [PubMed] [Google Scholar]

[R313] 313.Martin LJ, Liu Z. Opportunities for neuroprotection in ALS using cell death mechanism rationales. Drug Discov Today. 2004;1:135–43. [Google Scholar]

[R314] 314.Ginsberg SD, Hemby SE, Mufson EJ, Martin LJ. Cell and tissue microdissection in combination with genomic and proteomic profiling. In: Zaborszky L, Wouterlood FG, Lanciego JL, editors. Neuroanatomical tract-tracing 3, molecules, neurons, and systems. Springer; New York: 2006. pp. 109–41. [Google Scholar]

[R315] 315.Martin LJ. p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis. Neurobiol Dis. 2000;7:613–22. doi: 10.1006/nbdi.2000.0314. [DOI] [PubMed] [Google Scholar]

[R316] 316.Martin LJ. The apoptosis-necrosis cell death continuum in CNS development, injury and disease: contributions and mechanisms. In: Lo EH, Marwah J, editors. Neuroprotection. Prominent Press; Scottsdale, AZ: 2002. pp. 379–412. [Google Scholar]

[R317] 317.Martin LJ, Price AC, Kaiser A, Shaikh AY, Liu Z. Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death. Int J Mol Med. 2000;5:3–13. doi: 10.3892/ijmm.5.1.3. [DOI] [PubMed] [Google Scholar]

[R318] 318.Liu Z, Martin LJ. Motor neurons rapidly accumulate DNA single-strand breaks after in vitro exposure to nitric oxide and peroxynitrite and in vivo axotomy. J Comp Neurol. 2001;432:35–60. doi: 10.1002/cne.1087. [DOI] [PubMed] [Google Scholar]

[R319] 319.Wong M, Martin LJ. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet. 2010;9:2284–302. doi: 10.1093/hmg/ddq106. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R320] 320.Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol. 2008;85:94–134. doi: 10.1016/j.pneurobio.2008.01.001. [DOI] [PubMed] [Google Scholar]

[R321] 321.McCord JM, Fridovich I. Superoxide dismutase, an enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244:6049–55. [PubMed] [Google Scholar]

[R322] 322.Rakhit R, Crow JP, Lepock JR, Kondejewski LH, Cashman NR, Chakrabartty A. Monomeric Cu, Zn-superoxide dismutase is a common misfolding intermediate in the oxidation models of sporadic and familial amyotrophic sclerosis. J Biol Chem. 2004;279:15499–504. doi: 10.1074/jbc.M313295200. [DOI] [PubMed] [Google Scholar]

[R323] 323.Ferri A, Cozzolino M, Crosio C, Nencini M, Casciati A, Gralla EB, et al. Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. Proc Natl Acad Sci USA. 2006;103:13860–5. doi: 10.1073/pnas.0605814103. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R324] 324.Estévez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, Richardson GJ, et al. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science. 1999;286:2498–500. doi: 10.1126/science.286.5449.2498. [DOI] [PubMed] [Google Scholar]

[R325] 325.Flanagan SW, Anderson RD, Ross MA, Oberley LW. Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Znsuperoxide dismutase. J Neurochem. 2002;81:170–7. doi: 10.1046/j.1471-4159.2002.00812.x. [DOI] [PubMed] [Google Scholar]

[R326] 326.Bilsland LG, Nirmalananthan N, Yip J, Greensmith L, Duhcen MR. Expression of mutant SOD1G93A in astrocytes induces functional deficits in motoneuron mitochondria. J Neurochem. 2008;107:1271–83. doi: 10.1111/j.1471-4159.2008.05699.x. [DOI] [PubMed] [Google Scholar]

[R327] 327.Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5. doi: 10.1126/science.8209258. [DOI] [PubMed] [Google Scholar]

[R328] 328.Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol. 1994;145:1271–9. [PMC free article] [PubMed] [Google Scholar]

[R329] 329.Chang Q, Martin LJ. Glycinergic innervation of motoneurons is deficient in amyotrophic lateral sclerosis mice: a confocal quantitative analysis. Am J Pathol. 2009;174:574–85. doi: 10.2353/ajpath.2009.080557. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R330] 330.Bendotti C, Calvaresi N, Chiveri L, Prelle A, Moggio M, Braga M, et al. Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity. J Neurol Sci. 2001;191:25–33. doi: 10.1016/s0022-510x(01)00627-x. [DOI] [PubMed] [Google Scholar]

[R331] 331.Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995;14:1105–16. doi: 10.1016/0896-6273(95)90259-7. [DOI] [PubMed] [Google Scholar]

[R332] 332.Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998;18:3241–50. doi: 10.1523/JNEUROSCI.18-09-03241.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R333] 333.Jaarsma D, Rognoni F, van Duijn W, Verspaget HW, Haasdijk ED, Holstege JC. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. 2001;102:293–305. doi: 10.1007/s004010100399. [DOI] [PubMed] [Google Scholar]

[R334] 334.Sasaki S, Warita H, Murakami T, Abe K, Iwata M. Ultrastructural study of mitochondria in the spinal cord of transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathol. 2004;107:461–74. doi: 10.1007/s00401-004-0837-z. [DOI] [PubMed] [Google Scholar]

[R335] 335.Borchelt DR, Lee MK, Slunt HH, Guarnieri M, Xu Z-S, Wong PC, et al. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci USA. 1994;91:8292–6. doi: 10.1073/pnas.91.17.8292. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R336] 336.Yim MB, Kang J-H, Yim H-S, Kwak H-S, Chock PB, Stadtman ER. A gain-of-function of an amyotrophic lateral sclerosis-associated Cu, Zn-superoxide dismutase mutant: an enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. Proc Natl Acad Sci USA. 1996;93:5709–14. doi: 10.1073/pnas.93.12.5709. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R337] 337.Kabashi E, Valdmanis PN, Dion P, Rouleau GA. Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis? Ann Neurol. 2007;62:553–9. doi: 10.1002/ana.21319. [DOI] [PubMed] [Google Scholar]

[R338] 338.Ezzi SA, Urushitani M, Julien J-P. Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J Neurochem. 2007;102:170–8. doi: 10.1111/j.1471-4159.2007.04531.x. [DOI] [PubMed] [Google Scholar]

[R339] 339.Liochev SI, Fridovich I. Mutant Cu, Zn superoxide dismutases and familial amyotrophic lateral sclerosis: evaluation of oxidative hypotheses. Free Radic Biol Med. 2003;34:1383–9. doi: 10.1016/s0891-5849(03)00153-9. [DOI] [PubMed] [Google Scholar]

[R340] 340.Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315–424. doi: 10.1152/physrev.00029.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R341] 341.Andrus PK, Fleck TJ, Gurney ME, Hall ED. Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem. 1998;71:2041–8. doi: 10.1046/j.1471-4159.1998.71052041.x. [DOI] [PubMed] [Google Scholar]

[R342] 342.Poon HF, Hensley K, Thongboonkerd V, Merchant ML, Lynn BC, Pierce WM, et al. Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—a model of familial amyotrophic lateral sclerosis. Free Radic Biol Med. 2005;39:435–62. doi: 10.1016/j.freeradbiomed.2005.03.030. [DOI] [PubMed] [Google Scholar]

[R343] 343.Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide (SOD) in rat liver. J Biol Chem. 2001;276:38388–93. doi: 10.1074/jbc.M105395200. [DOI] [PubMed] [Google Scholar]

[R344] 344.Higgins CMJ, Jung C, Ding H, Xu Z. Mutant Cu Zn Superoxide dismutase that causes motoneuron degeneration is present in mitochondria in the CNS. J Neurosci. 2002;22(RC215):1–6. doi: 10.1523/JNEUROSCI.22-06-j0001.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R345] 345.Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, et al. Amyotrophic lateral sclerosis-associated SOD1 mutant protein bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004;43:19–30. doi: 10.1016/j.neuron.2004.06.021. [DOI] [PubMed] [Google Scholar]

[R346] 346.Goldsteins G, Keksa-Goldsteine V, Ahtiniemi T, Jaronen M, Arens E, Akerman K, et al. Deleterious role of superoxide dismutase in the mitochondrial intermembrane space. J Biol Chem. 2008;283:8446–52. doi: 10.1074/jbc.M706111200. [DOI] [PubMed] [Google Scholar]

[R347] 347.Higgins CM, Jung C, Xu Z. ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 2003;4:16. doi: 10.1186/1471-2202-4-16. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R348] 348.De Vos KJ, Chapman AL, Tennant ME, Manser C, Tudor EL, Lau K-F, et al. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondrial content. Hum Mol Genet. 2007;16:2720–8. doi: 10.1093/hmg/ddm226. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R349] 349.Martin LJ, Chen K, Liu Z. Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation. J Neurosci. 2005;25:6449–59. doi: 10.1523/JNEUROSCI.0911-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R350] 350.Siklos L, Engelhardt JI, Alexianu ME, Gurney ME, Siddique T, Appel SH. Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice. J Neuropathol Exp Neurol. 1998;57:571–87. doi: 10.1097/00005072-199806000-00005. [DOI] [PubMed] [Google Scholar]

[R351] 351.Jaiswal MK, Keller BU. Cu/Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of mitochondria and perturbs Ca2+ homeostasis in SOD1G93A mice. Mol Pharmacol. 2009;75:478–89. doi: 10.1124/mol.108.050831. [DOI] [PubMed] [Google Scholar]

[R352] 352.Nguyen KT, Garcia-Chacon LE, Barrett JN, Barrett EF, David G. The ψm depolarization that accompanies mitochondrial Ca2+ uptake is greater in mutant SOD1 than in wild-type mouse motor terminals. Proc Natl Acad Sci USA. 2009;106:2007–11. doi: 10.1073/pnas.0810934106. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R353] 353.Sasaki S, Shibata N, Komori T, Iwata M. iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis. Neurosci Lett. 2000;291:44–8. doi: 10.1016/s0304-3940(00)01370-7. [DOI] [PubMed] [Google Scholar]

[R354] 354.Martin LJ. Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010;13:568–80. [PMC free article] [PubMed] [Google Scholar]

[R355] 355.Kunz WS. Different metabolic properties of mitochondrial oxidative phosphorylation in different cell types—important implications for mitochondrial cytopathies. Exp Physiol. 2003;88(1):149–54. doi: 10.1113/eph8802512. [DOI] [PubMed] [Google Scholar]

[R356] 356.Keep M, Elmér E, Fong KSK, Csiszar K. Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Brain Res. 2001;894:27–331. doi: 10.1016/s0006-8993(01)02012-1. [DOI] [PubMed] [Google Scholar]

[R357] 357.Karlsson J, Fong KS, Hansson MJ, Elmer E, Csiszar K, Keep MF. Life span extension and reduced neuronal death after weekly intraventricular cyclosporine injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis. J Neurosurg. 2004;101:128–37. doi: 10.3171/jns.2004.101.1.0128. [DOI] [PubMed] [Google Scholar]

[R358] 358.Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT. An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment. J Neurochem. 2004;88:821–6. doi: 10.1046/j.1471-4159.2003.02181.x. [DOI] [PubMed] [Google Scholar]

[R359] 359.Bordet T, Buisson B, Michaud M, Drouot C, Galea P, Delaage P, et al. Identification and characterization of Cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007;322:709–20. doi: 10.1124/jpet.107.123000. [DOI] [PubMed] [Google Scholar]

[R360] 360.Mills C, Makwana M, Wallace A, Benn S, Schmidt H, Tegeder I, et al. Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats. Eur J Neurosci. 2008;27:937–46. doi: 10.1111/j.1460-9568.2008.06065.x. [DOI] [PubMed] [Google Scholar]

[R361] 361.Yan L-J, Sohal RS. Mitochondrial adenine nucleotide translocase is modified oxidatively during aging. Proc Natl Acad Sci USA. 1998;95:12896–901. doi: 10.1073/pnas.95.22.12896. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R362] 362.Prokai L, Yan L-J, Vera-Serrano JL, Stevens SM, Jr., Forster MJ. Mass spectrometry-based survey of age-associated protein carbonylation in rat brain mitochondria. J Mass Spectrom. 2007;42:1583–9. doi: 10.1002/jms.1345. [DOI] [PubMed] [Google Scholar]

[R363] 363.Vieira HLA, Belzacq A-S, Haouzu D, Bernassola F, Cohen I, Jacotot E, et al. The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene. 2001;20:4305–16. doi: 10.1038/sj.onc.1204575. [DOI] [PubMed] [Google Scholar]

[R364] 364.McStay GP, Clarke SJ, Halestrap AP. Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J. 2002;367:541–8. doi: 10.1042/BJ20011672. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R365] 365.Trumbull KA, Beckman JS. A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis. Antioxid Redox Signal. 2009;11:1627–39. doi: 10.1089/ars.2009.2574. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R366] 366.Costantini P, Belzacq A-S, Vieira HLA, Larochette N, de Pablo MA, Zamzami N, et al. Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis. Oncogene. 2000;19:307–14. doi: 10.1038/sj.onc.1203299. [DOI] [PubMed] [Google Scholar]

[R367] 367.García N, Martínez-Abundis E, Pavón N, Correa F, Chávez E. Copper induces permeability transition through its interaction with the adenine nucleotide translocase. Cell Biol Int. 2007;31:893–9. doi: 10.1016/j.cellbi.2007.02.003. [DOI] [PubMed] [Google Scholar]

[R368] 368.Grimm S, Brdiczka D. The permeability transition pore in cell death. Apoptosis. 2007;12:841–55. doi: 10.1007/s10495-007-0747-3. [DOI] [PubMed] [Google Scholar]

[R369] 369.Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, et al. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc Natl Acad Sci USA. 2007;104:7558–63. doi: 10.1073/pnas.0702228104. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R370] 370.Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci USA. 2005;102:12005–10. doi: 10.1073/pnas.0505294102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R371] 371.Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomized trial. Lancet Neurol. 2007;6:1045–53. doi: 10.1016/S1474-4422(07)70270-3. [DOI] [PubMed] [Google Scholar]

[R372] 372.Simon-Sanchez J, Singleton AB. Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. Hum Mol Genet. 2008;17:1988–93. doi: 10.1093/hmg/ddn096. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R373] 373.Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton M, Sudhof TC. α-Synulcein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663–7. doi: 10.1126/science.1195227. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R374] 374.Garcia-Reitbock P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E, Ghetti B, et al. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain. 2010;133:2032–44. doi: 10.1093/brain/awq132. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Biology of Mitochondria in Neurodegenerative Diseases

Lee J Martin

Abstract

I. Introduction

Fig 1.

Fig 2.

II. Some Aspects of Mitochondrial Biology Relevant to Neurodegeneration

A. Mitochondria and ROS

B. Mitochondria and Ca2+ Buffering

C. Mitochondrial DNA

D. DNA Repair in Mitochondria

E. Mitochondrial Trafficking and Cytoskeletal Motor Proteins for Mitochondria

III. Mitochondria and Cell Death

A. Mitochondrial Regulation of Apoptosis

TABLE I.

Fig 3.

TABLE II.

B. Apoptosis-Inducing Factor

C. Cell Death by Necrosis and the Mitochondrial Permeability Transition Pore

IV. Mitochondrial Autophagy

V. Mitochondrial Fission and Fusion

VI. Mitochondrial Involvement in Adult-Onset Neurodegenerative Diseases

A. Alzheimer's Disease

Fig 4.

B. Parkinson's Disease

Fig 5.

C. Gene Mutations that Cause Some Forms of PD

1. α-Synuclein

2. UCHL1 and Parkin

3. PINK1

4. DJ-1

5. LRRK2

D. PD α-Syn Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death

E. Amyotrophic Lateral Sclerosis

Fig 6.

TABLE III.

F. Mitochondrial Dysfunction in Human ALS

G. Human ALS and Mitochondrial-Orchestrated PCD Involving p53

H. Mitochondrial Pathobiology in Cell and Mouse Models of ALS

I. The MPTP Contributes to the Disease Mechanisms of ALS in Mice

VII. Reflections

Acknowledgments

Abbreviations

References

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

B. Mitochondria and Ca²⁺ Buffering