TABLE 1.
Drug Target Characteristics of Neurodegenerative Disease Gene Products
| Familial Disease | Disease Gene Product | Cellular Function | Role as Target |
|---|---|---|---|
| Disorders with Aberrant Protein Aggregation | |||
| Alzheimer’s disease | Presenilin-1 and 2 | Proposed aspartyl proteases; component of γ-secretase complex | Small molecule targets-protease inhibitors |
| Amyloid precursor protein (Aβ) | Unknown | Antibody target (Aβ1–42); target for aggregation inhibitors | |
| Familial British/Danish dementia | Bri2 | Unknown | |
| Frontotemporal dementia (FTDP-17) | tau | Microtubule assembly and stability | |
| Prion diseases | PrPac | Unknown | Small molecule target-pathogenic conformation inhibitors |
| Familial encephalopathy with neuroserpin inclusion bodies (FENIB) | Neuroserpin | Serine protease inhibitor | |
| Parkinson’s disease* | α-Synuclein | Unknown; roles in presynaptic function | |
| Huntington’s disease | Huntingtin | Unknown; putative roles in vesicle recycling, transcription | |
| Amyotrophic lateral sclerosis | Cu, Zn SOD1 | Superoxide metabolism | |
| Hereditary spastic paraplegia-SPG4 | Spastin | Role in microtubule dynamics | |
| Dentatorubropallidoluysian atrophy (DRPLA) | DRPLA (atrophin-1) | Unknown | |
| Spinobulbar muscular atrophy | Androgen receptor | Ligand-activated transcription factor | Small molecule target-ligand antagonists |
| Spinocerebellar ataxias 1, 2, 3, 7, 10 | Ataxins-1, -2, -3, -7, -10 | Roles in gene regulation | |
| SCA6 | CACNA1A | Ca2+ channel α 1a subunit | |
| SCA14 | Protein kinase C γ | Protein kinase C γ | |
| SCA17 | TATA binding protein | Transcriptional regulator | |
| Lafora disease | Laforin | Dual specificity phosphatase | |
| Malin | E3 ubiquitin ligase | ||
| Fragile X-associated tremor/ataxia syndrome (FXTAS) | FMR1 | RNA binding protein | |
| Disorders with Mitochondrion-Targeted Disease Gene Products | |||
| Wilson’s disease† | ATP7B | P-type (copper transporting) ATPase | None; decoppering therapy |
| Fredereich’s ataxia | Frataxin | Iron homcostasis; heme synthesis | |
| Mohr-Tranebjaerg syndrome | Deafness/dystonia protein-1 (TIMM8A) | Unknown | |
| Parkinson’s disease | Pink1 | Putative protein kinase | |
| Hereditary spastic paraplegia SPG7 | Paraplegin | Putative ATP-dependent protease | |
| Hereditary spastic paraplegia SPG13 | HSP60 | Mitochondrial import chaperonin | |
| Motor neuron disease | Cytochrome c oxidase 1 | Electron transport | |
| LHON | mitochondrial complex I subunits | Mitochondrial energy metabolism | |
| Disorders with Defects in DNA Damage Repair | |||
| Ataxia telangiectasia | ATM | Protein kinase | Small molecule target-kinase activators |
| Ataxia telangiectasia-like disease | MRE11 | Component of DNA double-stranded break sensor complex | |
| Nijmegen breakage syndrome | Nibrin | Component of DNA double-stranded break sensor complex | |
| Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) | TDP1 | Tyrosyl phosphodiesterase | |
| Ataxia with oculomotor apraxia 1 | Aprataxin | Component of DNA repair complex for single-stranded breaks | |
| Ataxia with oculomotor apraxia 2 | Senataxin‡ | Putative role in DNA repair | |
Notes: Lysosomal storage disorders (not listed above) form a fourth class of neurodegenerative diseases that contains a large collection of over 48 distinct types resulting from defects in lysosomal membrane transporters and hydrolases; these are largely neurodevelopmental disorders of childhood.
*
Familial PD is caused by several additional genes, including UCHL1, LRRK2, DJ1, and Parkin. Lewy body pathology has not been definitively associated with any of these familial forms.
†
Wilson’s disease gene product, ATP7B, is found in other subcellular compartments in addition to the mitochondrion.
‡
Mutant SETX alleles were identified as the cause of a juvenile form of ALS.67