Molecular pathways of neurodegeneration in Parkinson's disease.
Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause alpha-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of alpha-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and alpha-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
Dawson
Ted M
TM
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. tdawson@jhmi.edu
Dawson
Valina L
VL
D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D051843:Synucleins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein
D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D042967:Electron Transport Complex I; D004298:Dopamine