New insights into Parkinson's disease.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Recent advances in genetics and pathophysiology have led to new insights into the pathogenesis of PD. Ten loci have been linked to hereditary PD. Mutations in alpha-synuclein and ubiquitin carboxy hydrolase L1 (UchL1) cause autosomal dominant PD and mutations in parkin and DJ-1 cause autosomal recessive PD. alpha-Synuclein has emerged as an important protein in the pathogenesis of PD, as it appears to be the major structural component of Lewy bodies and its accumulation/aggregation seems to play a prominent role in sporadic PD. Mutations in parkin are the most common cause of hereditary PD, and mutations in parkin are thought to lead to a loss of parkin's ubiquitin E3 ligase activity. Derangements in parkin function as well as mutations in UCH-L1 fit with the notion that derangements in the ubiquitin proteasomal pathway (UPP) may play important roles in the demise of dopamine neurons in PD. DJ-1 is a protein of unknown function that is linked to autosomal recessive PD. Oxidative stress and impairment in mitochondrial complex I activity are important in sporadic PD, and there is emerging interest in the role of herbicides, fungicides and insecticides that inhibit mitochondrial complex I activity and their role in contributing to the development of PD. These important findings serve as the foundation for discovering new pathways that may lead to the development of new therapies for PD.
Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Carnegie 2-214, Baltimore, Maryland 21287, USA.
Kenny K K
KK
Chung
Valina L
VL
Dawson
Ted M
TM
Dawson
D000818:Animals; D004781:Environmental Exposure; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D051843:Synucleins; D025801:Ubiquitin / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein