Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Jul 1.
Published in final edited form as: Brain Res Bull. 2016 Dec 23;133:51–59. doi: 10.1016/j.brainresbull.2016.12.004

Parkin and PINK1 functions in oxidative stress and neurodegeneration

Sandeep K Barodia 1, Rose B Creed 1, Matthew S Goldberg 1,2,*
PMCID: PMC5718625  NIHMSID: NIHMS844948  PMID: 28017782

Abstract

Loss-of-function mutations in the genes encoding Parkin and PINK1 are causally linked to autosomal recessive Parkinson’s disease (PD). Parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial-targeted kinase, function together in a common pathway to remove dysfunctional mitochondria by autophagy. Presumably, deficiency for Parkin or PINK1 impairs mitochondrial autophagy and thereby increases oxidative stress due to the accumulation of dysfunctional mitochondria that release reactive oxygen species. Parkin and PINK1 likely have additional functions that may be relevant to the mechanisms by which mutations in these genes cause neurodegeneration, such as regulating inflammation, apoptosis, or dendritic morphogenesis. Here we briefly review what is known about functions of Parkin and PINK1 related to oxidative stress and neurodegeneration.

Keywords: PINK1, Parkin, Ubiquitin, Neurodegeneration, Oxidative stress, Mitophagy

1. Introduction

Oxidative stress has been implicated as a likely cause of many neurodegenerative diseases including Parkinson’s disease (PD). PD is the most common neurodegenerative movement disorder and affects millions of people worldwide. PD is defined clinically by bradykinesia, resting tremor, rigidity and abnormal gait. It is diagnosed neuropathologically by relatively selective loss of dopaminergic neurons in the substantia nigra and the presence of Lewy body intraneuronal inclusions containing α-synuclein. Current pharmacological therapies treat the symptoms, mostly by enhancing dopaminergic signaling, which is required for normal movement. There are currently no therapies proven to slow down disease progression or to protect against neurodegeneration. Most PD cases are sporadic, but the recent identification of genes with mutations linked to familial forms of PD provides important clues that could help determine the causes of both familial and idiopathic PD, and could lead to the development of more effective therapies (Kumaran and Cookson 2015). Even prior to the identification of the first genetic mutations linked to PD, mitochondrial dysfunction and oxidative stress were implicated in PD pathogenesis because neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), can induce parkinsonism in humans and animal models by inhibiting mitochondrial respiration and increasing production of reactive oxygen species (ROS) (Langston 1987; Mizuno et al. 1995; Jenner and Olanow 1996; Fukae et al. 2007; Zhou et al. 2008; Camilleri and Vassallo 2014; Gautier et al. 2014; Moon and Paek 2015). Even under normal physiological conditions, electron leakage from the mitochondrial electron transport chain is a major cellular source of ROS that damage proteins, lipids and DNA (Beal 2005). Because this damage likely accumulates with age and because age is the greatest PD risk factor, mitochondrial dysfunction and oxidative stress are likely causes of idiopathic PD initiation and progression (Beal 2003; Shults 2004). Consistent with this, oxidatively damaged subunits of mitochondrial complex I are increased in PD brains (Keeney et al. 2006) and impaired complex I activity has been observed in multiple tissues and peripheral blood leukocytes from PD patients (Mann et al. 1992; Albers and Beal 2000; Muftuoglu et al. 2004; Schapira 2008). Perhaps the most compelling evidence for mitochondrial dysfunction as a direct cause of parkinsonism (rather than a consequence or an age-coupled epiphenomenon) comes from the genetic linkage of loss-of-function mutations in the mitochondrial kinase Phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) to early onset recessive parkinsonism (Valente et al. 2004). PINK1 is a mitochondrial kinase that accumulates on the surface of defective mitochondria and recruits Parkin to promote selective degradation of dysfunctional mitochondria (Narendra et al. 2008; Matsuda et al. 2010). Loss-of-function mutations in Parkin account for about 50% of all cases of early onset PD (Kitada et al. 1998; Lucking et al. 2000). Here, we briefly review the known functions of PINK1 and Parkin with respect to potential mechanisms of PD pathogenesis.

2. Mitochondrial dysfunction and oxidative stress in PD

The single greatest risk factor for PD is age, which strongly implicates cumulative oxidative damage as a causative mechanism. There is now overwhelming evidence that oxidative damage plays a key role in idiopathic PD and inherited parkinsonism, as well as neurotoxin-induced PD animal models (Fahn and Cohen 1992; Cassarino et al. 1997; Beal 2005). Low-level oxidative stress may promote mitochondrial biogenesis and elimination or repair of damaged mitochondria while high-level oxidative stress beyond the cellular capacity to repair or remove oxidative damage may lead to the accumulation of damaged mitochondria (Lee and Wei 2005). Of all the proteins with mutations so far linked to parkinsonism, Parkin is one of the most sensitive to oxidation and mounting evidence suggests Parkin is important for protecting cells from oxidative stress (Hyun et al. 2002; Palacino et al. 2004; Pesah et al. 2004; Greene et al. 2005). Observations that Parkin is sensitive to oxidative damage by nitrosylation supports the idea that oxidative damage to endogenous Parkin may contribute to idiopathic PD (Yao et al. 2004). Dopamine readily oxidizes to form reactive oxygen species and dopamine quinone, which can covalently modify and inactivate Parkin, providing further evidence that progressive loss of Parkin function in dopamine neurons in combination with oxidative stress may contribute to onset or progression of idiopathic PD (LaVoie et al. 2005). Although inherited mutations in Parkin cause only a small fraction of all clinical parkinsonism cases, oxidative damage to Parkin protein is observed in the brains of sporadic PD patients, which supports the hypothesis that inactivation of Parkin in conjunction with oxidative damage could cause idiopathic PD (Chung et al. 2004; Yao et al. 2004).

3. Mutations in Parkin and PINK1 causally linked to PD

Mutations in five genes have so far been definitively linked to familial PD. Gain-of-function mutations in α-synuclein and LRRK2 have been linked to dominantly inherited parkinsonism (Polymeropoulos et al. 1997; Paisan-Ruiz et al. 2004; Zimprich et al. 2004), and loss-of-function mutations in parkin, DJ-1, and PINK1 have been linked to recessively inherited parkinsonism (Kitada et al. 1998; Bonifati et al. 2003; Valente et al. 2004).

Parkin was the first gene to be identified with mutations linked to recessive parkinsonism (Kitada et al. 1998). Over 100 different parkin mutations affecting each of parkin’s 12 exons have since been identified in parkinsonian patients, including missense point mutations, truncation mutations, large chromosomal deletions and duplications spanning one or more exons, as well as promoter mutations (Hedrich et al. 2004; Lesage et al. 2007). The recessive mode of inheritance and the absence of Parkin protein (or radically truncated protein in some patients) are consistent with a loss-of-function mechanism by which parkin gene mutations cause disease (Shimura et al. 1999). Parkin is expressed widely throughout the brain and other tissues, with the highest mRNA abundance in brain, heart and skeletal muscle (Kitada et al. 1998).

Loss-of-function mutations in parkin are found in nearly 50% of parkinsonism cases with onset of symptoms before age 45 (Lucking et al. 2000). Other than an earlier average age at onset, the clinical symptoms of patients bearing parkin mutations resembles that of typical late-onset idiopathic PD, with good therapeutic response to L-DOPA and slightly slower disease progression (Lucking et al. 2000). There is so much overlap in clinical symptoms between idiopathic PD and parkin-linked disease that it is not possible to distinguish patients bearing parkin mutations from idiopathic PD based on clinical criteria alone (Lucking et al. 2000). Although parkin mutations were first identified in patients with very young age at onset, parkin mutations have since been identified in typical late-onset PD patients and parkin polymorphisms or heterozygous mutations are suspected of increasing susceptibility to typical late-onset PD (Klein et al. 2000; Schlitter et al. 2006). Parkin polymorphisms, in combination with increased environmental exposures to substances suspected of causing idiopathic PD, are associated with earlier onset of symptoms more than either factor alone (Ghione et al. 2007).

The initial neuropathological examinations reported for cases bearing parkin mutations led to the assumption that Parkin is required for Lewy body formation because no Lewy bodies were observed in the initial autopsies, however, Lewy bodies have since been observed in cases from 2 independent families bearing parkin mutations (Farrer et al. 2001; Pramstaller et al. 2005). All autopsies of parkin-linked PD showed profound loss of neuromelanin-containing neurons in the substantia nigra pars compacta as well as prominent loss of locus coeruleus neurons, which is also observed in idiopathic PD. Given that cortical Lewy bodies are commonly observed in neuropathological examinations of aged brains, it is likely that the absence of Lewy bodies in some cases of parkin-linked PD reflects the earlier age at onset of these cases and the many years or decades that may be required for insoluble protein aggregates to accumulate to the extent that they can be detected by visible light microscopy in the form of Lewy bodies. We and others have put forward the hypothesis that small protein aggregates are more likely to be mechanistically involved in PD pathogenesis than Lewy bodies or large fibrillar aggregates that can be detected by microscopy (Goldberg and Lansbury 2000). We speculate that parkin and PINK1 function, at least in part, to prevent the accumulation of small protein aggregates or oxidized proteins that could be neurotoxic.

Loss-of-function mutations in PINK1 cause clinical symptoms and neuropathology indistinguishable from PD with young onset (Valente et al. 2004; Samaranch et al. 2010). PINK1 was first cloned in the course of a search for genes upregulated by the tumor suppressor gene PTEN (Unoki and Nakamura 2001). Loss-of-function mutations in PINK1 were subsequently identified as the cause of recessive parkinsonism linked to the PARK6 locus on chromosome 1 (Valente et al. 2004). The PINK1 gene contains 8 exons encoding a 581 amino acid protein with an N-terminal mitochondrial targeting motif, a transmembrane domain (amino acids 94–110) and a highly conserved kinase domain (amino acids 156–509) with sequence homology to the serine/threonine kinases of the calcium/calmodulin family (Valente et al. 2004). PINK1 is ubiquitously expressed throughout the human and rodent brain (including in the substantia nigra) (Taymans et al. 2006; Blackinton et al. 2007) and in most adult human tissues, but at higher levels in skeletal muscle and heart (Unoki and Nakamura 2001).

Over 50 mutations causally linked to recessive parkinsonism have been identified throughout the length of the PINK1 gene (Kawajiri et al. 2011) (Figure 1). These include missense point mutations, truncating mutations, genomic rearrangements and whole gene deletions. The penetrance of homozygous mutations is very high and heterozygous mutations may increase susceptibility for PD (Kawajiri et al. 2011). The clinical features of PINK1-linked parkinsonism are indistinguishable from sporadic PD with the exception of an earlier age of onset and slower progression (Kawajiri et al. 2011). Postmortem examination of PINK1-linked PD shows neuropathology similar to idiopathic PD with Lewy bodies and neuronal loss in the substantia nigra accompanied by microgliosis and astrocytic gliosis (Samaranch et al. 2010; Steele et al. 2015), although Lewy bodies were not observed in one of the three autopsies reported to date (Takanashi et al. 2016).

Figure 1.

Figure 1

Open in a new tab

Primary sequence domain structure of PINK1 and common point mutations linked to PD. PINK1 domains are annotated as follows: mitochondrial targeting sequence (MTS, blue); transmembrane helix (TM, yellow); N-terminal regulatory region (NT, gray); kinase domain consisting of N- and C-terminal lobes (green and light gray, respectively), and a C-terminal domain (CTD, orange). The amino acid residue numbers at the beginning and end of each domain are shown on the top. Some of the more common missense and nonsense mutations are shown on the bottom.

4. Domain structures and functions of Parkin and PINK1

PINK1 encodes a kinase with a mitochondrial targeting sequence at the N-terminus. PINK1 is normally rapidly degraded following mitochondrial import, however, low mitochondrial membrane potential induced by treating cells with ionophores, such as CCCP or valinomycin, causes PINK1 to accumulate on the outer mitochondrial membrane and to recruit Parkin to selectively target dysfunctional mitochondria for degradation by autophagy (Narendra et al. 2008; Matsuda et al. 2010; Narendra et al. 2010). Autophagy is a highly regulated and conserved process of lysosomal-mediated protein degradation and recycling of organelles. Mitochondria can be degraded by autophagy either non-selectively or selectively in a process termed mitophagy in which defective mitochondria (e.g. with low membrane potential) are selectively targeted for degradation (Figure 2). This can promote cell survival by removing dysfunctional mitochondria that produce excess reactive oxygen species via leakage from the electron transport chain and by removing mitochondria that might otherwise signal apoptosis. The prevailing hypothesis regarding the mechanisms by which loss-of-function mutations in PINK1 and Parkin cause PD is that deficiency for either Parkin or PINK1 diminishes mitophagy and causes an age-dependent accumulation of dysfunctional mitochondria that would otherwise be removed, leading to increased ROS and to eventual neurodegeneration of susceptible cells (Figure 2).

Figure 2.

Figure 2

Open in a new tab

Proposed normal functions of PINK1 and Parkin (top) and possible mechanisms of neurodegeneration cause by PINK1-deficiency (PINK1 −/−) or Parkin-deficiency (Parkin −/−). PINK1 protein is targeted to mitochondria but normally rapidly degraded. PINK1 protein accumulates on the outer membrane of mitochondria with reduced or absent membrane potential. PINK1 recruits Parkin from the cytosol to the mitochondrial outer membrane. PINK1 also activates Parkin by phosphorylation of serine 65 on Parkin and serine 65 on ubiquitin. The E3 ubiquitin ligase activity of Parkin targets mitochondria for degradation by autophagy. The selective autophagy of dysfunctional mitochondria via the combined activities of PINK1 and Parkin may be important for removing a major cellular source of reactive oxygen species (ROS) that can damage proteins, lipids and DNA. In the absence of PINK1 or Parkin, the accumulation of dysfunctional mitochondria over time may lead to increased ROS and eventually cause neurodegeneration, such as loss of dopamine neurons in the substantia nigra or other vulnerable cell populations.

PINK1 null Drosophila exhibit striking mitochondrial morphology defects, flight muscle degeneration, male sterility and mitochondrial respiration defects that precede the prominent visible flight muscle pathology, suggesting that the mitochondrial defects constitute an early pathogenic mechanism (Clark et al. 2006; Park et al. 2006; Yang et al. 2006). Some, but not all, groups have observed degeneration of dopamine neurons in PINK1 null flies (Clark et al. 2006; Park et al. 2006; Yang et al. 2006). Notably, Parkin null Drosophila have the same phenotype and the muscle degeneration and mitochondrial morphology defects in PINK1 null Drosophila can be rescued by overexpression of Parkin, consistent with Parkin functioning downstream of PINK1 in the same pathway (Clark et al. 2006; Park et al. 2006; Yang et al. 2006). Similar to Parkin knockout mice (Goldberg et al. 2003), PINK1 knockout mice do not develop nigral dopamine neuron loss but exhibit mitochondrial respiration defects in the striatum but not in the cortex at 3–4 months (Kitada et al. 2007; Zhou et al. 2007; Gispert et al. 2009; Akundi et al. 2011). Multiple groups have reported significant nigral cell loss in 8–9 month old PINK1 knockout rats using rigorous stereology (Dave et al. 2014; Villeneuve et al. 2014).

The parkin gene encodes a cytosolic 465 amino-acid protein with a ubiquitin-like (Ubl) domain at the N-terminus and an RBR (RING-between-RING) domain toward the C-terminus (Shimura et al. 2000) (Figure 3). Parkin functions as an E3 ubiquitin ligase (Shimura et al. 2000) and it has been shown to be capable of inducing monoubiquitination (Hampe et al. 2006; Moore et al. 2008), multiple monoubiquitination (Matsuda et al. 2006), as well as K48-linked and K63-linked polyubiquitination (Doss-Pepe et al. 2005; Lim et al. 2005). Parkin has been demonstrated to bind to several E2 ubiquitin conjugating proteins including UbcH7, UbcH8, and a UbcH13/Uev1a heterodimer that is thought to be responsible for the catalysis of K63-linked ubiquitin chains (Shimura et al. 2000; Zhang et al. 2000; Olzmann et al. 2007). In addition to the more common K48-linked and K63-linked ubiquitin chains, Parkin can also form K11 and K6 linked chains (Ordureau et al. 2014). Parkin itself becomes ubiquitinated by the attachment of K6 ubiquitin chains, which may play a role in its own degradation (Durcan et al. 2014).

Figure 3.

Figure 3

Open in a new tab

Primary sequence domain structure of Parkin and common point mutations linked to PD. Parkin domains are annotated as follows: ubiquitin like domain (Ubl, orange); really interesting new gene (RING0, RING1 and RING2, green, blue and brown, respectively); In between RING domain (IBR, gray); repressor domain (REP, pink). The amino acid residue numbers at each domain border are shown on the top. Some of the more common missense and nonsense mutations are shown on the bottom. In addition to point mutations, large deletions and duplications of one or more exons are also common.

Parkin has been shown to translocate from the cytosol to mitochondria upon mitochondrial depolarization (Narendra et al. 2008) and to ubiquitinate various proteins including mitochondrial outer membrane proteins such as VDAC1, Mfn1/2, Miro, Hexokinase I, CISD1, and TOMM20 (Weihofen et al. 2009; Gegg et al. 2010; Geisler et al. 2010; Poole et al. 2010; Ziviani et al. 2010; Chan et al. 2011; Glauser et al. 2011; Kane and Youle 2011; Rakovic et al. 2011; Wang et al. 2011; Okatsu et al. 2012; Koyano et al. 2013; Sarraf et al. 2013; Ordureau et al. 2014). Parkin translocation to depolarized mitochondria and Parkin-mediated ubiquitination of mitochondrial proteins correlates with induction of mitochondrial autophagy even in cells lacking PINK1 (Kubli et al. 2015). The Ubl domain is not necessary for the E3-ligase activity of Parkin in vitro because a C-terminal fragment of Parkin is capable of auto-ubiquitination (Matsuda et al. 2006). Furthermore, deletion of the Ubl domain actually increases Parkin auto-ubiquitination, consistent with the Ubl domain functioning as a constitutive inhibitor of Parkin’s E3 ligase activity (Chaugule et al. 2011).

Crystal and NMR structures of Parkin show that Parkin protein exists in an auto-inhibited state (Riley et al. 2013; Spratt et al. 2013; Trempe et al. 2013; Wauer and Komander 2013). This detailed structural knowledge has enabled the generation of Parkin variants, such as W403A, that alleviate the auto-inhibition of Parkin and promote Parkin E3 ubiquitin ligase activity in cell-based and cell-free in vitro assays (Riley et al. 2013; Trempe et al. 2013; Koyano et al. 2014; Zhang et al. 2014; Fiesel et al. 2015b; Koyano and Matsuda 2015). Parkin has been found to be activated by PINK1-mediated phosphorylation at serine 65 (S65) within the Ubl domain (Kondapalli et al. 2012; Shiba-Fukushima et al. 2012) and by binding to serine 65-phosphorylated ubiquitin (Kane et al. 2014; Kazlauskaite et al. 2014b; Koyano et al. 2014). More recent crystal and NMR structures have revealed mechanisms by which phosphorylation of Parkin at S65 and binding to S65-phosphorylated ubiquitin induce Parkin activation by decreasing the interactions that mediate Parkin auto-inhibition (Caulfield et al. 2014; Caulfield et al. 2015; Fiesel et al. 2015b; Koyano and Matsuda 2015; Kumar et al. 2015; Sauve et al. 2015; Wauer et al. 2015a) (Figure 4). This knowledge will hopefully expedite the discovery and development of Parkin-activating drugs as potential PD therapeutics that could reduce ROS by enhancing Parkin-mediated autophagy of dysfunctional mitochondria. Additional potential therapeutic mechanisms are discussed below.

Figure 4.

Figure 4

Open in a new tab

Tertiary protein domain structure of Parkin highlighting interactions involved in regulating E3 ligase activity. PINK1 phosphorylates Parkin at serine 65, which causes a conformational change and activates Parkin by removing auto-inhibition mediated by the Ubl domain and REP domain of Parkin. PINK1 also phosphorylates ubiquitin at serine 65, which binds to Parkin and activates Parkin’s E3 ubiquitin ligase activity. The locations of the E2 binding site and the catalytic cysteine (C431) are also shown.

5. Alternative functions and potential pathogenic mechanisms

There is compelling evidence that PINK1 and Parkin can function in a common pathway because Parkin overexpression can rescue the mitochondrial dysfunction and flight muscle degeneration phenotypes of PINK1 null Drosophila (Clark et al. 2006; Park et al. 2006; Yang et al. 2006) and because PINK1-mediated phosphorylation of Parkin at serine 65 activates Parkin in vitro and PINK1-phosphorylated ubiquitin chains function both as receptors for recruiting Parkin from the cytosol to the mitochondrial outer membrane and as enhancers of Parkin’s E3 ligase activity (Kondapalli et al. 2012; Shiba-Fukushima et al. 2012; Caulfield et al. 2014; Kane et al. 2014; Kazlauskaite et al. 2014a; Kazlauskaite et al. 2014b; Koyano et al. 2014; Ordureau et al. 2014; Sauve and Gehring 2014; Shiba-Fukushima et al. 2014; Caulfield et al. 2015; Fiesel et al. 2015a; Kazlauskaite et al. 2015; Okatsu et al. 2015a; Okatsu et al. 2015b; Ordureau et al. 2015a; Ordureau et al. 2015b; Wauer et al. 2015a; Wauer et al. 2015b; Zheng and Hunter 2015). Nevertheless, multiple groups have published data indicating that PINK1 and Parkin can also function independently and in other pathways. For example, it has been shown that PINK1 can recruit the autophagy receptors NDP52 and optineurin directly to mitochondria to activate mitophagy independent of Parkin (Lazarou et al. 2015).

Although much of the recent research on the cellular functions of Parkin and PINK1 has focused on mitochondrial autophagy (Pickrell and Youle 2015), there is no definitive evidence that the mechanism by which loss-of-function mutations in Parkin and PINK1 cause PD involves defective mitophagy. Many of the same proteins that govern autophagy and mitophagy, including Parkin and PINK1, are also involved in adaptive and innate immunity (Dzamko et al. 2015; Netea-Maier et al. 2015). Mutations in Parkin and PINK1 increase susceptibility to inflammation, which may be the mechanism by which loss-of-function mutations in Parkin and PINK1 cause PD (Frank-Cannon et al. 2008; Akundi et al. 2011) (Table 1). Parkin knockout mice have significantly increased susceptibility to nigral dopamine neuron loss induced by chronic peripheral low dose lipopolysaccharide (LPS) administration, which mimics chronic inflammation (Frank-Cannon et al. 2008). There is a Nuclear Factor-Kappa B (NF-kB) response element in the parkin promoter that represses parkin transcription, indicating that chronic inflammation can reduce Parkin levels similar to Parkin mutations that cause PD (Tran et al. 2011). Activated macrophages from Parkin-deficient mice have increased expression of pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) and IL-1b as well as iNOS (Tran et al. 2011). Furthermore, Parkin-deficient mice have mitochondrial respiration defects within the nigrostriatal pathway and increased markers of reactive oxygen species, which can also activate inflammatory pathways and increase pro-inflammatory cytokines (Palacino et al. 2004). Similar mitochondrial defects were subsequently reported in cells from patients bearing PD-linked mutations in Parkin, suggesting that this mechanism could be operative in humans (Muftuoglu et al. 2004; Mortiboys et al. 2008). Similar to Parkin, PINK1 likely regulates inflammatory cytokine production (Akundi et al. 2011). Transcriptional profiling of PINK1 knockout mouse striatum showed that the largest number of genes with altered expression were those that regulate innate immune responses (Akundi et al. 2011) (Table 1). Consistent with this, peripheral LPS treatment induced higher brain levels of inflammatory cytokines in PINK1 knockout mice compared to controls (Akundi et al. 2011).

Table 1.

Phenotypes of PINK1 and Parkin genetic models.

Gene Animal Manipulation DA neuron loss DA responsive motor deficits Immune or inflammatory effects References
Parkin
(PARK2)		 C. elegans Knockout No No ND1 Springer et al. 2005
Drosophila Knockout Yes Yes ND1 Greene et al. 2003, Whitworth et al. 2005
Transgenic Yes Yes ND1 Wang et al. 2007, Sang et al. 2007
Mouse Knockout No ND1 Yes Goldberg et al. 2003, Itier et al. 2003, Von Coelln et al. 2004, Perez et al. 2005, Frank Cannon et al. 2008.
Transgenic Yes ND1 ND1 Lu et al. 2009.
Rat Knockout Yes Yes ND1 Dave et al. 2014
PINK1
(PARK6)		 Drosophila Knockout Yes ND1 Park et al. 2006, Clark et al. 2006
Mouse Knockout No Yes Yes Kitada et al. 2007, Gautier et al. 2008, Gispert et al. 2009, Akundi et al. 2011.
Rat Knockout Yes Yes ND1 Dave et al. 2014
Open in a new tab
1

ND: Not determined

Recently, it has been shown that Parkin and PINK1 repress mitochondrial antigen presentation by actively inhibiting the formation of mitochondrial-derived vesicles (MDVs), which are required for mitochondrial antigen presentation independent of mitochondrial autophagy (Matheoud et al. 2016). This data suggests that Parkin and PINK1 function as suppressors of an inflammation-induced immune response pathway. It is noteworthy that Parkin inhibits the mitochondrial recruitment of Rab9 and Sorting nexin 9, which are required for the formation of MDVs and mitochondrial autophagy (Matheoud et al. 2016).

Phosphoproteomic studies identified Rab proteins as direct and indirect targets of PINK1 kinase activity independent of Parkin (Lai et al. 2015). Specifically, even in cells lacking Parkin (but not in cells lacking PINK1), PINK1 activation by mitochondrial depolarization increased phosphorylation of Rab8A, Rab8B and Rab13 at the highly conserved serine 111 (Lai et al. 2015). This suggests that PINK1 can function independently of Parkin to regulate specific Rab GTPase family members that are known to regulate secretory pathways, such as Rab 8A, 8B and 13. It had previously been shown that Rab7, together with its GTPase activating proteins TBC1D15 and TBC1D17, are required for Parkin-mediated mitophagy downstream of PINK1-induced Parkin translocation to mitochondria (Yamano et al. 2014). Together, this highlights the likely possibility that PINK1 and Parkin have both dependent and independent functions and the possibility that some of these functions are distinct from mitochondrial autophagy. Additional examples of independent and distinct functions include Parkin regulation of mitochondrial cytochrome c release, BAX translocation to mitochondria, and apoptosis (Berger et al. 2009; Johnson et al. 2012a; Johnson et al. 2012b; Charan et al. 2014), and PINK1 regulation of neuronal dendritic morphology (Dagda et al. 2014).

6. PINK1 and Parkin in other neurodegenerative diseases

Mitochondrial dysfunction has been implicated in many neurodegenerative diseases, which has prompted investigations of PINK1 and Parkin beyond Parkinson’s research. Analysis of human Alzheimer’s’ disease and multiple sclerosis brains shows increased levels of PINK1 in a cell type specific manner (Wilhelmus et al. 2011). Fibroblasts from AD patients show slower mitochondrial membrane potential recovery post insult, alterations in lysosomal and autophagic pathways, increased reactive oxygen species, and protein aggregation (Martin-Maestro et al. 2016). These were attributed to impairment of PINK1-Parkin mediated mitophagy and could be rescued by Parkin overexpression (Martin-Maestro et al. 2016). PINK1-Parkin pathway alterations have also been found in other neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Huntington’s disease (HD). It has been recently reported that ALS patients have lower mRNA levels of PINK1 in affected muscles, which suggest a role for PINK1 in ALS progression (Knippenberg et al. 2013). Mitophagy has been shown to be altered in HD and overexpression of PINK1 is able to rescue HD phenotypes in fly and mouse models of HD (Khalil et al. 2015).

6. Therapeutic implications

Increased expression of Parkin protects against cell death induced by various stress conditions, such as mitochondrial stress, endoplasmic reticulum stress, excitotoxicity, and proteotoxic stress (Imai et al. 2000; Petrucelli et al. 2002; Darios et al. 2003; Staropoli et al. 2003; Higashi et al. 2004; Jiang et al. 2004; Muqit et al. 2004; Yang et al. 2005; Rosen et al. 2006; Fett et al. 2010). Parkin overexpression also has been shown to protect against nigral dopamine neuron loss in animal models of PD (Lo Bianco et al. 2004; Vercammen et al. 2006; Ulusoy and Kirik 2008; Bian et al. 2012). Parkin gene expression is upregulated under cellular stress, and transcription factors such as ATF4 and p53 can increase Parkin expression, whereas c-Jun and N-myc act as transcriptional repressors of Parkin (West et al. 2004; Bouman et al. 2011; Zhang et al. 2011). Parkin also has been found to regulate several cell viability pathways including JNK, PI3K and NF-κB signaling, p53 transcriptional activity, and Bax activation (Cha et al. 2005; Yang et al. 2005; Henn et al. 2007; Hasegawa et al. 2008; da Costa et al. 2009; Sha et al. 2010; Johnson et al. 2012a)

Parkin displays a low basal E3 ubiquitin ligase activity and a small increase in the activation of Parkin could be sufficient to slow the progression of PD in sporadic forms of the disease in which the wild type protein is present. Small molecules that mimic phospho-ubiquitin or disrupt autoinhibitory interactions might enhance Parkin’s neuroprotective action. In cultured cells, mutation of Trp403 or Phe463 speeds recruitment of Parkin to mitochondria in a regulated process that remains dependent on PINK1 and mitochondrial depolarization (Trempe et al. 2013). A small molecule that binds tightly to the pocket occupied by the amino acid side chains would be expected to have the same effect. The deubiquitinating enzymes (DUBs) USP30 and USP15 were recently found to oppose Parkin/PINK1 mediated mitophagy, suggesting that inhibitors of these DUBs would be good candidates for drug design (Bingol et al. 2014; Cornelissen et al. 2014). In contrast, USP8 promotes Parkin mediated mitophagy and agonists to USP8 could be developed as potential therapeutics (Durcan et al. 2014). PINK1 has been shown to activate Parkin both by direct phosphorylation and by phosphorylating ubiquitin (Kondapalli et al. 2012; Shiba-Fukushima et al. 2012; Caulfield et al. 2014; Kane et al. 2014; Kazlauskaite et al. 2014a; Kazlauskaite et al. 2014b; Koyano et al. 2014; Ordureau et al. 2014; Sauve and Gehring 2014; Shiba-Fukushima et al. 2014; Caulfield et al. 2015; Fiesel et al. 2015a; Kazlauskaite et al. 2015; Okatsu et al. 2015a; Okatsu et al. 2015b; Ordureau et al. 2015a; Ordureau et al. 2015b; Wauer et al. 2015a; Wauer et al. 2015b; Zheng and Hunter 2015). This suggests that enhancing PINK1 abundance or PINK1 kinase activity may be another potential option for therapeutic development. In spite of many challenges, PINK1 and Parkin appear to offer multiple promising therapeutic targets for the treatment of PD and relevant diseases caused by mitochondrial dysfunction and oxidative stress.

Highlights (for review).

  • -

    Mutations in PINK1 and Parkin are linked to Parkinson’s disease

  • -

    PINK1 and Parkin are believed to function in a common pathway in mitochondrial autophagy

  • -

    Additional potential functions of PINK1 and Parkin are reviewed

Acknowledgments

This work was supported by grants from the Michael J. Fox Foundation for Parkinson’s Research and by the National Institute of Neurological Disorders and Stroke under NIH award number R01NS082565. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. Akundi RS, Huang Z, Eason J, et al. Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS One. 2011;6:e16038. doi: 10.1371/journal.pone.0016038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albers DS, Beal MF. Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm Suppl. 2000;59:133–154. doi: 10.1007/978-3-7091-6781-6_16. [DOI] [PubMed] [Google Scholar]
  3. Beal MF. Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann N Y Acad Sci. 2003;991:120–131. doi: 10.1111/j.1749-6632.2003.tb07470.x. [DOI] [PubMed] [Google Scholar]
  4. Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. 2005;58:495–505. doi: 10.1002/ana.20624. [DOI] [PubMed] [Google Scholar]
  5. Berger AK, Cortese GP, Amodeo KD, Weihofen A, Letai A, LaVoie MJ. Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release. Hum Mol Genet. 2009;18:4317–4328. doi: 10.1093/hmg/ddp384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bian M, Liu J, Hong X, et al. Overexpression of parkin ameliorates dopaminergic neurodegeneration induced by 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. PLoS One. 2012;7:e39953. doi: 10.1371/journal.pone.0039953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bingol B, Tea JS, Phu L, et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature. 2014;510:370–375. doi: 10.1038/nature13418. [DOI] [PubMed] [Google Scholar]
  8. Blackinton JG, Anvret A, Beilina A, Olson L, Cookson MR, Galter D. Expression of PINK1 mRNA in human and rodent brain and in Parkinson’s disease. Brain Res. 2007;1184:10–16. doi: 10.1016/j.brainres.2007.09.056. [DOI] [PubMed] [Google Scholar]
  9. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299:256–259. doi: 10.1126/science.1077209. [DOI] [PubMed] [Google Scholar]
  10. Bouman L, Schlierf A, Lutz AK, et al. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ. 2011;18:769–782. doi: 10.1038/cdd.2010.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Camilleri A, Vassallo N. The centrality of mitochondria in the pathogenesis and treatment of Parkinson’s disease. CNS Neurosci Ther. 2014;20:591–602. doi: 10.1111/cns.12264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cassarino DS, Fall CP, Swerdlow RH, et al. Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson’s disease. Biochim Biophys Acta. 1997;1362:77–86. doi: 10.1016/s0925-4439(97)00070-7. [DOI] [PubMed] [Google Scholar]
  13. Caulfield TR, Fiesel FC, Moussaud-Lamodiere EL, Dourado DF, Flores SC, Springer W. Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase Parkin. PLoS Comput Biol. 2014;10:e1003935. doi: 10.1371/journal.pcbi.1003935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Caulfield TR, Fiesel FC, Springer W. Activation of the E3 ubiquitin ligase Parkin. Biochem Soc Trans. 2015;43:269–274. doi: 10.1042/BST20140321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cha GH, Kim S, Park J, et al. Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci U S A. 2005;102:10345–10350. doi: 10.1073/pnas.0500346102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Chan NC, Salazar AM, Pham AH, et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet. 2011;20:1726–1737. doi: 10.1093/hmg/ddr048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Charan RA, Johnson BN, Zaganelli S, Nardozzi JD, LaVoie MJ. Inhibition of apoptotic Bax translocation to the mitochondria is a central function of parkin. Cell Death Dis. 2014;5:e1313. doi: 10.1038/cddis.2014.278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ, Shaw GS, Walden H. Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO J. 2011;30:2853–2867. doi: 10.1038/emboj.2011.204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Chung KK, Thomas B, Li X, et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science. 2004;304:1328–1331. doi: 10.1126/science.1093891. [DOI] [PubMed] [Google Scholar]
  20. Clark IE, Dodson MW, Jiang C, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006 doi: 10.1038/nature04779. [DOI] [PubMed] [Google Scholar]
  21. Cornelissen T, Haddad D, Wauters F, et al. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum Mol Genet. 2014;23:5227–5242. doi: 10.1093/hmg/ddu244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. da Costa CA, Sunyach C, Giaime E, et al. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson’s disease. Nat Cell Biol. 2009;11:1370–1375. doi: 10.1038/ncb1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Dagda RK, Pien I, Wang R, et al. Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A. J Neurochem. 2014;128:864–877. doi: 10.1111/jnc.12494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Darios F, Corti O, Lucking CB, et al. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet. 2003;12:517–526. doi: 10.1093/hmg/ddg044. [DOI] [PubMed] [Google Scholar]
  25. Dave KD, De Silva S, Sheth NP, et al. Phenotypic characterization of recessive gene knockout rat models of Parkinson’s disease. Neurobiol Dis. 2014;70:190–203. doi: 10.1016/j.nbd.2014.06.009. [DOI] [PubMed] [Google Scholar]
  26. Doss-Pepe EW, Chen L, Madura K. Alpha-synuclein and parkin contribute to the assembly of ubiquitin lysine 63-linked multiubiquitin chains. J Biol Chem. 2005;280:16619–16624. doi: 10.1074/jbc.M413591200. [DOI] [PubMed] [Google Scholar]
  27. Durcan TM, Tang MY, Perusse JR, et al. USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. EMBO J. 2014;33:2473–2491. doi: 10.15252/embj.201489729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Dzamko N, Geczy CL, Halliday GM. Inflammation is genetically implicated in Parkinson’s disease. Neuroscience. 2015;302:89–102. doi: 10.1016/j.neuroscience.2014.10.028. [DOI] [PubMed] [Google Scholar]
  29. Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol. 1992;32:804–812. doi: 10.1002/ana.410320616. [DOI] [PubMed] [Google Scholar]
  30. Farrer M, Chan P, Chen R, et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol. 2001;50:293–300. doi: 10.1002/ana.1132. [DOI] [PubMed] [Google Scholar]
  31. Fett ME, Pilsl A, Paquet D, et al. Parkin is protective against proteotoxic stress in a transgenic zebrafish model. PLoS One. 2010;5:e11783. doi: 10.1371/journal.pone.0011783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Fiesel FC, Ando M, Hudec R, et al. (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO Rep. 2015a;16:1114–1130. doi: 10.15252/embr.201540514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Fiesel FC, Caulfield TR, Moussaud-Lamodiere EL, et al. Structural and Functional Impact of Parkinson Disease-Associated Mutations in the E3 Ubiquitin Ligase Parkin. Hum Mutat. 2015b;36:774–786. doi: 10.1002/humu.22808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Frank-Cannon TC, Tran T, Ruhn KA, et al. Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci. 2008;28:10825–10834. doi: 10.1523/JNEUROSCI.3001-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Fukae J, Mizuno Y, Hattori N. Mitochondrial dysfunction in Parkinson’s disease. Mitochondrion. 2007;7:58–62. doi: 10.1016/j.mito.2006.12.002. [DOI] [PubMed] [Google Scholar]
  36. Gautier CA, Corti O, Brice A. Mitochondrial dysfunctions in Parkinson’s disease. Rev Neurol (Paris) 2014;170:339–343. doi: 10.1016/j.neurol.2013.06.003. [DOI] [PubMed] [Google Scholar]
  37. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010;19:4861–4870. doi: 10.1093/hmg/ddq419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin- mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12:119–131. doi: 10.1038/ncb2012. [DOI] [PubMed] [Google Scholar]
  39. Ghione I, Di Fonzo A, Saladino F, Del Bo R, Bresolin N, Comi GP, Rango M. Parkin polymorphisms and environmental exposure: Decrease in age at onset of Parkinson’s disease. Neurotoxicology. 2007 doi: 10.1016/j.neuro.2007.01.004. [DOI] [PubMed] [Google Scholar]
  40. Gispert S, Ricciardi F, Kurz A, et al. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One. 2009;4:e5777. doi: 10.1371/journal.pone.0005777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Glauser L, Sonnay S, Stafa K, Moore DJ. Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J Neurochem. 2011;118:636–645. doi: 10.1111/j.1471-4159.2011.07318.x. [DOI] [PubMed] [Google Scholar]
  42. Goldberg MS, Fleming SM, Palacino JJ, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 2003;278:43628–43635. doi: 10.1074/jbc.M308947200. [DOI] [PubMed] [Google Scholar]
  43. Goldberg MS, Lansbury PT., Jr Is there a cause-and-effect relationship between alpha-synuclein fibrillization and Parkinson’s disease? Nat Cell Biol. 2000;2:E115–119. doi: 10.1038/35017124. [DOI] [PubMed] [Google Scholar]
  44. Greene JC, Whitworth AJ, Andrews LA, Parker TJ, Pallanck LJ. Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum Mol Genet. 2005;14:799–811. doi: 10.1093/hmg/ddi074. [DOI] [PubMed] [Google Scholar]
  45. Hampe C, Ardila-Osorio H, Fournier M, Brice A, Corti O. Biochemical analysis of Parkinson’s disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum Mol Genet. 2006;15:2059–2075. doi: 10.1093/hmg/ddl131. [DOI] [PubMed] [Google Scholar]
  46. Hasegawa T, Treis A, Patenge N, Fiesel FC, Springer W, Kahle PJ. Parkin protects against tyrosinase-mediated dopamine neurotoxicity by suppressing stress-activated protein kinase pathways. J Neurochem. 2008;105:1700–1715. doi: 10.1111/j.1471-4159.2008.05277.x. [DOI] [PubMed] [Google Scholar]
  47. Hedrich K, Eskelson C, Wilmot B, et al. Distribution, type, and origin of Parkin mutations: review and case studies. Mov Disord. 2004;19:1146–1157. doi: 10.1002/mds.20234. [DOI] [PubMed] [Google Scholar]
  48. Henn IH, Bouman L, Schlehe JS, et al. Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J Neurosci. 2007;27:1868–1878. doi: 10.1523/JNEUROSCI.5537-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Higashi Y, Asanuma M, Miyazaki I, Hattori N, Mizuno Y, Ogawa N. Parkin attenuates manganese-induced dopaminergic cell death. J Neurochem. 2004;89:1490–1497. doi: 10.1111/j.1471-4159.2004.02445.x. [DOI] [PubMed] [Google Scholar]
  50. Hyun DH, Lee M, Hattori N, Kubo S, Mizuno Y, Halliwell B, Jenner P. Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J Biol Chem. 2002;277:28572–28577. doi: 10.1074/jbc.M200666200. [DOI] [PubMed] [Google Scholar]
  51. Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem. 2000;275:35661–35664. doi: 10.1074/jbc.C000447200. [DOI] [PubMed] [Google Scholar]
  52. Jenner P, Olanow CW. Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology. 1996;47:S161–170. doi: 10.1212/wnl.47.6_suppl_3.161s. [DOI] [PubMed] [Google Scholar]
  53. Jiang H, Ren Y, Zhao J, Feng J. Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum Mol Genet. 2004;13:1745–1754. doi: 10.1093/hmg/ddh180. [DOI] [PubMed] [Google Scholar]
  54. Johnson BN, Berger AK, Cortese GP, Lavoie MJ. The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax. Proc Natl Acad Sci U S A. 2012a;109:6283–6288. doi: 10.1073/pnas.1113248109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Johnson BN, Charan RA, LaVoie MJ. Recognizing the cooperative and independent mitochondrial functions of Parkin and PINK1. Cell Cycle. 2012b;11:2775–2776. doi: 10.4161/cc.21261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Kane LA, Lazarou M, Fogel AI, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205:143–153. doi: 10.1083/jcb.201402104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Kane LA, Youle RJ. PINK1 and Parkin flag Miro to direct mitochondrial traffic. Cell. 2011;147:721–723. doi: 10.1016/j.cell.2011.10.028. [DOI] [PubMed] [Google Scholar]
  58. Kawajiri S, Saiki S, Sato S, Hattori N. Genetic mutations and functions of PINK1. Trends Pharmacol Sci. 2011;32:573–580. doi: 10.1016/j.tips.2011.06.001. [DOI] [PubMed] [Google Scholar]
  59. Kazlauskaite A, Kelly V, Johnson C, et al. Phosphorylation of Parkin at Serine65 is essential for activation: elaboration of a Miro1 substrate-based assay of Parkin E3 ligase activity. Open Biol. 2014a;4:130213. doi: 10.1098/rsob.130213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Kazlauskaite A, Kondapalli C, Gourlay R, et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014b;460:127–139. doi: 10.1042/BJ20140334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Kazlauskaite A, Martinez-Torres RJ, Wilkie S, et al. Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Rep. 2015;16:939–954. doi: 10.15252/embr.201540352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Keeney PM, Xie J, Capaldi RA, Bennett JP., Jr Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 2006;26:5256–5264. doi: 10.1523/JNEUROSCI.0984-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Khalil B, El Fissi N, Aouane A, Cabirol-Pol MJ, Rival T, Lievens JC. PINK1-induced mitophagy promotes neuroprotection in Huntington’s disease. Cell Death Dis. 2015;6:e1617. doi: 10.1038/cddis.2014.581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–608. doi: 10.1038/33416. [DOI] [PubMed] [Google Scholar]
  65. Kitada T, Pisani A, Porter DR, et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A. 2007;104:11441–11446. doi: 10.1073/pnas.0702717104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Klein C, Pramstaller PP, Kis B, et al. Parkin deletions in a family with adult-onset, tremor- dominant parkinsonism: expanding the phenotype. Ann Neurol. 2000;48:65–71. [PubMed] [Google Scholar]
  67. Knippenberg S, Sipos J, Thau-Habermann N, Korner S, Rath KJ, Dengler R, Petri S. Altered expression of DJ-1 and PINK1 in sporadic ALS and in the SOD1(G93A) ALS mouse model. J Neuropathol Exp Neurol. 2013;72:1052–1061. doi: 10.1097/NEN.0000000000000004. [DOI] [PubMed] [Google Scholar]
  68. Kondapalli C, Kazlauskaite A, Zhang N, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012;2:120080. doi: 10.1098/rsob.120080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Koyano F, Matsuda N. Molecular mechanisms underlying PINK1 and Parkin catalyzed ubiquitylation of substrates on damaged mitochondria. Biochim Biophys Acta. 2015 doi: 10.1016/j.bbamcr.2015.02.009. [DOI] [PubMed] [Google Scholar]
  70. Koyano F, Okatsu K, Ishigaki S, et al. The principal PINK1 and Parkin cellular events triggered in response to dissipation of mitochondrial membrane potential occur in primary neurons. Genes Cells. 2013;18:672–681. doi: 10.1111/gtc.12066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014;510:162–166. doi: 10.1038/nature13392. [DOI] [PubMed] [Google Scholar]
  72. Kubli DA, Cortez MQ, Moyzis AG, Najor RH, Lee Y, Gustafsson AB. PINK1 Is Dispensable for Mitochondrial Recruitment of Parkin and Activation of Mitophagy in Cardiac Myocytes. PLoS One. 2015;10:e0130707. doi: 10.1371/journal.pone.0130707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Kumar A, Aguirre JD, Condos TE, et al. Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. EMBO J. 2015 doi: 10.15252/embj.201592337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Kumaran R, Cookson MR. Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson’s disease. Hum Mol Genet. 2015;24:R32–44. doi: 10.1093/hmg/ddv236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Lai YC, Kondapalli C, Lehneck R, et al. Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. EMBO J. 2015;34:2840–2861. doi: 10.15252/embj.201591593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Langston JW. MPTP: insights into the etiology of Parkinson’s disease. Eur Neurol. 1987;26(Suppl 1):2–10. doi: 10.1159/000116349. [DOI] [PubMed] [Google Scholar]
  77. LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ. Dopamine covalently modifies and functionally inactivates parkin. Nat Med. 2005;11:1214–1221. doi: 10.1038/nm1314. [DOI] [PubMed] [Google Scholar]
  78. Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524:309–314. doi: 10.1038/nature14893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Lee HC, Wei YH. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol. 2005;37:822–834. doi: 10.1016/j.biocel.2004.09.010. [DOI] [PubMed] [Google Scholar]
  80. Lesage S, Magali P, Lohmann E, et al. Deletion of the parkin and PACRG gene promoter in early-onset parkinsonism. Hum Mutat. 2007;28:27–32. doi: 10.1002/humu.20436. [DOI] [PubMed] [Google Scholar]
  81. Lim KL, Chew KC, Tan JM, et al. Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci. 2005;25:2002–2009. doi: 10.1523/JNEUROSCI.4474-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Lo Bianco C, Schneider BL, Bauer M, Sajadi A, Brice A, Iwatsubo T, Aebischer P. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci U S A. 2004;101:17510–17515. doi: 10.1073/pnas.0405313101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. French Parkinson’s Disease Genetics Study Group. N Engl J Med. 2000;342:1560–1567. doi: 10.1056/NEJM200005253422103. [DOI] [PubMed] [Google Scholar]
  84. Mann VM, Cooper JM, Krige D, Daniel SE, Schapira AH, Marsden CD. Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson’s disease. Brain. 1992;115(Pt 2):333–342. doi: 10.1093/brain/115.2.333. [DOI] [PubMed] [Google Scholar]
  85. Martin-Maestro P, Gargini R, Perry G, Avila J, Garcia-Escudero V. PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer’s disease. Hum Mol Genet. 2016;25:792–806. doi: 10.1093/hmg/ddv616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Matheoud D, Sugiura A, Bellemare-Pelletier A, et al. Parkinson’s Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation. Cell. 2016 doi: 10.1016/j.cell.2016.05.039. [DOI] [PubMed] [Google Scholar]
  87. Matsuda N, Kitami T, Suzuki T, Mizuno Y, Hattori N, Tanaka K. Diverse effects of pathogenic mutations of Parkin that catalyze multiple monoubiquitylation in vitro. J Biol Chem. 2006;281:3204–3209. doi: 10.1074/jbc.M510393200. [DOI] [PubMed] [Google Scholar]
  88. Matsuda N, Sato S, Shiba K, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 2010;189:211–221. doi: 10.1083/jcb.200910140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Mizuno Y, Ikebe S, Hattori N, Nakagawa-Hattori Y, Mochizuki H, Tanaka M, Ozawa T. Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim Biophys Acta. 1995;1271:265–274. doi: 10.1016/0925-4439(95)00038-6. [DOI] [PubMed] [Google Scholar]
  90. Moon HE, Paek SH. Mitochondrial Dysfunction in Parkinson’s Disease. Exp Neurobiol. 2015;24:103–116. doi: 10.5607/en.2015.24.2.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Moore DJ, West AB, Dikeman DA, Dawson VL, Dawson TM. Parkin mediates the degradation- independent ubiquitination of Hsp70. J Neurochem. 2008;105:1806–1819. doi: 10.1111/j.1471-4159.2008.05261.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Mortiboys H, Thomas KJ, Koopman WJ, et al. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol. 2008;64:555–565. doi: 10.1002/ana.21492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Muftuoglu M, Elibol B, Dalmizrak O, et al. Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov Disord. 2004;19:544–548. doi: 10.1002/mds.10695. [DOI] [PubMed] [Google Scholar]
  94. Muqit MM, Davidson SM, Payne Smith MD, et al. Parkin is recruited into aggresomes in a stress- specific manner: over-expression of parkin reduces aggresome formation but can be dissociated from parkin’s effect on neuronal survival. Hum Mol Genet. 2004;13:117–135. doi: 10.1093/hmg/ddh012. [DOI] [PubMed] [Google Scholar]
  95. Narendra D, Tanaka A, Suen DF, 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]
  96. Narendra DP, Jin SM, Tanaka A, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8:e1000298. doi: 10.1371/journal.pbio.1000298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Netea-Maier RT, Plantinga TS, Van De Veerdonk FL, Smit JW, Netea MG. Modulation of inflammation by autophagy: consequences for human disease. Autophagy. 2015;0 doi: 10.1080/15548627.2015.1071759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Okatsu K, Iemura S, Koyano F, et al. Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase. Biochem Biophys Res Commun. 2012;428:197–202. doi: 10.1016/j.bbrc.2012.10.041. [DOI] [PubMed] [Google Scholar]
  99. Okatsu K, Kimura M, Oka T, Tanaka K, Matsuda N. Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment. J Cell Sci. 2015a;128:964–978. doi: 10.1242/jcs.161000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Okatsu K, Koyano F, Kimura M, Kosako H, Saeki Y, Tanaka K, Matsuda N. Phosphorylated ubiquitin chain is the genuine Parkin receptor. J Cell Biol. 2015b;209:111–128. doi: 10.1083/jcb.201410050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007;178:1025–1038. doi: 10.1083/jcb.200611128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Ordureau A, Heo JM, Duda DM, et al. Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci U S A. 2015a;112:6637–6642. doi: 10.1073/pnas.1506593112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Ordureau A, Munch C, Harper JW. Quantifying ubiquitin signaling. Mol Cell. 2015b;58:660–676. doi: 10.1016/j.molcel.2015.02.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Ordureau A, Sarraf SA, Duda DM, et al. Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell. 2014;56:360–375. doi: 10.1016/j.molcel.2014.09.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Paisan-Ruiz C, Jain S, Evans EW, 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]
  106. Palacino JJ, Sagi D, Goldberg MS, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004;279:18614–18622. doi: 10.1074/jbc.M401135200. [DOI] [PubMed] [Google Scholar]
  107. Park J, Lee SB, Lee S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006 doi: 10.1038/nature04788. [DOI] [PubMed] [Google Scholar]
  108. Pesah Y, Pham T, Burgess H, et al. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development. 2004;131:2183–2194. doi: 10.1242/dev.01095. [DOI] [PubMed] [Google Scholar]
  109. Petrucelli L, O’Farrell C, Lockhart PJ, et al. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002;36:1007–1019. doi: 10.1016/s0896-6273(02)01125-x. [DOI] [PubMed] [Google Scholar]
  110. Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron. 2015;85:257–273. doi: 10.1016/j.neuron.2014.12.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–2047. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
  112. Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One. 2010;5:e10054. doi: 10.1371/journal.pone.0010054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Pramstaller PP, Schlossmacher MG, Jacques TS, et al. Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol. 2005;58:411–422. doi: 10.1002/ana.20587. [DOI] [PubMed] [Google Scholar]
  114. Rakovic A, Grunewald A, Kottwitz J, Bruggemann N, Pramstaller PP, Lohmann K, Klein C. Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts. PLoS One. 2011;6:e16746. doi: 10.1371/journal.pone.0016746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Riley BE, Lougheed JC, Callaway K, et al. Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat Commun. 2013;4:1982. doi: 10.1038/ncomms2982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Rosen KM, Veereshwarayya V, Moussa CE, et al. Parkin Protects against Mitochondrial Toxins and beta-Amyloid Accumulation in Skeletal Muscle Cells. J Biol Chem. 2006;281:12809–12816. doi: 10.1074/jbc.M512649200. [DOI] [PubMed] [Google Scholar]
  117. Samaranch L, Lorenzo-Betancor O, Arbelo JM, et al. PINK1-linked parkinsonism is associated with Lewy body pathology. Brain. 2010;133:1128–1142. doi: 10.1093/brain/awq051. [DOI] [PubMed] [Google Scholar]
  118. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature. 2013;496:372–376. doi: 10.1038/nature12043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Sauve V, Gehring K. Phosphorylated ubiquitin: a new shade of PINK1 in Parkin activation. Cell Res. 2014;24:1025–1026. doi: 10.1038/cr.2014.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Sauve V, Lilov A, Seirafi M, et al. A Ubl/ubiquitin switch in the activation of Parkin. EMBO J. 2015 doi: 10.15252/embj.201592237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008;7:97–109. doi: 10.1016/S1474-4422(07)70327-7. [DOI] [PubMed] [Google Scholar]
  122. Schlitter AM, Kurz M, Larsen JP, Woitalla D, Muller T, Epplen JT, Dekomien G. Parkin gene variations in late-onset Parkinson’s disease: comparison between Norwegian and German cohorts. Acta Neurol Scand. 2006;113:9–13. doi: 10.1111/j.1600-0404.2005.00532.x. [DOI] [PubMed] [Google Scholar]
  123. Sha D, Chin LS, Li L. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet. 2010;19:352–363. doi: 10.1093/hmg/ddp501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Shiba-Fukushima K, Arano T, Matsumoto G, et al. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 2014;10:e1004861. doi: 10.1371/journal.pgen.1004861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Shiba-Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, Hattori N. PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep. 2012;2:1002. doi: 10.1038/srep01002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25:302–305. doi: 10.1038/77060. [DOI] [PubMed] [Google Scholar]
  127. Shimura H, Hattori N, Kubo S, et al. Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients. Ann Neurol. 1999;45:668–672. doi: 10.1002/1531-8249(199905)45:5<668::aid-ana19>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  128. Shults CW. Mitochondrial dysfunction and possible treatments in Parkinson’s disease–a review. Mitochondrion. 2004;4:641–648. doi: 10.1016/j.mito.2004.07.028. [DOI] [PubMed] [Google Scholar]
  129. Spratt DE, Martinez-Torres RJ, Noh YJ, et al. A molecular explanation for the recessive nature of parkin-linked Parkinson’s disease. Nat Commun. 2013;4:1983. doi: 10.1038/ncomms2983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A. Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron. 2003;37:735–749. doi: 10.1016/s0896-6273(03)00084-9. [DOI] [PubMed] [Google Scholar]
  131. Steele JC, Guella I, Szu-Tu C, et al. Defining neurodegeneration on Guam by targeted genomic sequencing. Ann Neurol. 2015;77:458–468. doi: 10.1002/ana.24346. [DOI] [PubMed] [Google Scholar]
  132. Takanashi M, Li Y, Hattori N. Absence of Lewy pathology associated with PINK1 homozygous mutation. Neurology. 2016;86:2212–2213. doi: 10.1212/WNL.0000000000002744. [DOI] [PubMed] [Google Scholar]
  133. Taymans JM, Van den Haute C, Baekelandt V. Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem. 2006;98:951–961. doi: 10.1111/j.1471-4159.2006.03919.x. [DOI] [PubMed] [Google Scholar]
  134. Tran TA, Nguyen AD, Chang J, Goldberg MS, Lee JK, Tansey MG. Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B. PLoS One. 2011;6:e23660. doi: 10.1371/journal.pone.0023660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Trempe JF, Sauve V, Grenier K, et al. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science. 2013;340:1451–1455. doi: 10.1126/science.1237908. [DOI] [PubMed] [Google Scholar]
  136. Ulusoy A, Kirik D. Can overexpression of parkin provide a novel strategy for neuroprotection in Parkinson’s disease? Exp Neurol. 2008;212:258–260. doi: 10.1016/j.expneurol.2008.04.026. [DOI] [PubMed] [Google Scholar]
  137. Unoki M, Nakamura Y. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene. 2001;20:4457–4465. doi: 10.1038/sj.onc.1204608. [DOI] [PubMed] [Google Scholar]
  138. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304:1158–1160. doi: 10.1126/science.1096284. [DOI] [PubMed] [Google Scholar]
  139. Vercammen L, Van der Perren A, Vaudano E, Gijsbers R, Debyser Z, Van den Haute C, Baekelandt V. Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson’s disease. Mol Ther. 2006;14:716–723. doi: 10.1016/j.ymthe.2006.06.009. [DOI] [PubMed] [Google Scholar]
  140. Villeneuve LM, Purnell PR, Boska MD, Fox HS. Early Expression of Parkinson’s Disease-Related Mitochondrial Abnormalities in PINK1 Knockout Rats. Mol Neurobiol. 2014 doi: 10.1007/s12035-014-8927-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  141. Wang X, Winter D, Ashrafi G, et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell. 2011;147:893–906. doi: 10.1016/j.cell.2011.10.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  142. Wauer T, Komander D. Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J. 2013;32:2099–2112. doi: 10.1038/emboj.2013.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Wauer T, Simicek M, Schubert A, Komander D. Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature. 2015a;524:370–374. doi: 10.1038/nature14879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  144. Wauer T, Swatek KN, Wagstaff JL, et al. Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis. EMBO J. 2015b;34:307–325. doi: 10.15252/embj.201489847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  145. Weihofen A, Thomas KJ, Ostaszewski BL, Cookson MR, Selkoe DJ. Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry. 2009;48:2045–2052. doi: 10.1021/bi8019178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  146. West AB, Kapatos G, O’Farrell C, Gonzalez-de-Chavez F, Chiu K, Farrer MJ, Maidment NT. N-myc regulates parkin expression. J Biol Chem. 2004;279:28896–28902. doi: 10.1074/jbc.M400126200. [DOI] [PubMed] [Google Scholar]
  147. Wilhelmus MM, van der Pol SM, Jansen Q, et al. Association of Parkinson disease-related protein PINK1 with Alzheimer disease and multiple sclerosis brain lesions. Free Radic Biol Med. 2011;50:469–476. doi: 10.1016/j.freeradbiomed.2010.11.033. [DOI] [PubMed] [Google Scholar]
  148. Yamano K, Fogel AI, Wang C, van der Bliek AM, Youle RJ. Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. Elife. 2014;3:e01612. doi: 10.7554/eLife.01612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Yang H, Zhou HY, Li B, Chen SD. Neuroprotection of Parkin against apoptosis is independent of inclusion body formation. Neuroreport. 2005;16:1117–1121. doi: 10.1097/00001756-200507130-00017. [DOI] [PubMed] [Google Scholar]
  150. Yang Y, Gehrke S, Imai Y, et al. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A. 2006;103:10793–10798. doi: 10.1073/pnas.0602493103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  151. Yao D, Gu Z, Nakamura T, et al. Nitrosative stress linked to sporadic Parkinson’s disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A. 2004;101:10810–10814. doi: 10.1073/pnas.0404161101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  152. Zhang C, Lee S, Peng Y, et al. PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol. 2014;24:1854–1865. doi: 10.1016/j.cub.2014.07.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  153. Zhang C, Lin M, Wu R, et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci U S A. 2011;108:16259–16264. doi: 10.1073/pnas.1113884108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  154. Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A. 2000;97:13354–13359. doi: 10.1073/pnas.240347797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. Zheng X, Hunter T. How phosphoubiquitin activates Parkin. Cell Res. 2015;25:1087–1088. doi: 10.1038/cr.2015.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  156. Zhou C, Huang Y, Przedborski S. Oxidative stress in Parkinson’s disease: a mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci. 2008;1147:93–104. doi: 10.1196/annals.1427.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  157. Zhou H, Falkenburger BH, Schulz JB, Tieu K, Xu Z, Xia XG. Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci. 2007;3:242–250. doi: 10.7150/ijbs.3.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  158. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–607. doi: 10.1016/j.neuron.2004.11.005. [DOI] [PubMed] [Google Scholar]
  159. Ziviani E, Tao RN, Whitworth AJ. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci U S A. 2010;107:5018–5023. doi: 10.1073/pnas.0913485107. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES