[Pathogenesis of sporadic Parkinson's disease: contribution of genetic and environmental risk factors].
Parkinson's disease (PD) is the most common neurodegenerative disease after Alzheimer's disease. Although the pathogenetic mechanisms underlying PD is largely unknowm, it is widely believed that multiple genetic as well as environmental factors play critical roles in the development of PD. Alpha synuclein (a-SYN) and the disturbance of a-SYN metabolism seems to play the most important role in PD pathogenesis. a-SYN, the gene causative in PARK1, is the major component of Lewy bodies. Gene duplication or triplication of a-SYN leads to autosomal dominant form of familial PD, suggesting that disturbance of a-SYN may represent the etiology of sporadic PD. GBA and LRRK, the genes responsible for Gaucher disease and PARK8, respetively, are also likely to affect the development of PD. Studies of PD brains suggest that mitochondrial impairment and oxidative stress may contribute to the pathogenesis of sporadic PD. Mitochondrial complex I inhibitors, such as MPTP and rotenone, induce selective dopaminergic neuronal death, suggesting that chemicals may constitute risk factors of sporadic PD. Not only continuous infusion, but oral intake of rotenone is effective to establish animal models of PD. Further studies will reveal genetic or environmental risk factors, that are the good targets for prevention and therapy of PD.
Takahashi
Ryosuke
R
Department of Neurology, Kyoto University Graduate School of Medicine.
Kawamata
Jun
J
Takeuchi
Hiroki
H
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D005962:Glucosylceramidase / Q000235:genetics; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria; D009154:Mutation; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012307:Risk Factors; D012402:Rotenone; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein; D012402:Rotenone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005962:Glucosylceramidase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease