[Pathogenesis of Parkinson's disease: implications from familial Parkinson's disease]

The deposition of alpha-synuclein (aS), a product of pathogenic gene for dominantly inherited familial Parkinson's disease (PD; park1), as fibrillary aggregates like Lewy bodies (LB), is a hallmark lesion of a set of neurodegenerative disorders termed synucleinopathies, including sporadic PD and dementia with Lewy bodies (DLB). We found that aS is the major component of LBs and further identified a specific phosphorylation of Ser129 of insoluble aS by mass spectrometric analysis. The roles of DJ-1 and PINK-1, products of pathogenic genes for autosomal recessive forms of early-onset parkinsonism, have subsequently been examined. Overexpression of DJ-1 conferred cultured cells resistance to oxidative stress, suggesting an antioxidant function of DJ-1. We also confirmed the anti-PTEN function of DJ-1 that may promote cell survival, showing decreased phosphorylation of Akt through upregulation of PTEN activity upon siRNA knockdown for DJ-1. PINK-1, that had been identified as a gene upregulated by PTEN overexpression, turned out to be a protein kinase localized in mitochondria. Collectively, information derived from studies on pathogenic genes for familial PD will open up the way toward the clarification of the pathogenesis of PD, underscoring the roles of protein aggregation, proteolysis, oxidative stress and protein phosphorylation in PD.