Title "Molecular Pathogenesis of Parkinson's Disease"

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To elucidate the molecular pathogenesis of sporadic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), we examined the alterations, especially posttranslational modifications, of α-synuclein (aS) that gets deposited in affected neurons of PD and DLB as fibrillary aggregates represented by Lewy bodies (LB). We analyzed aS purified from insoluble fractions of DLB cortices and demonstrated by mass spectrometry that Ser129 of deposited aS is phosphorylated. Phosphorylated Ser129-specific antibody revealed extensive deposition of aS as intracellular inclusions like LBs, as well as thread-or dot-like deposits in degenerating neurites. A fraction of phosphorylated aS was mono-ubiquitinated at the N- terminal Lys residues. Proteinase K digestion of aS filaments showed that the mid-portion of aS comprises the protease-resistant core structure. Transgenic Drosophila expressing aS in neurons exhibited phosphorylation of aS in a subset of neurons. Co-expression of aS and synphilin-1 in mammalian cultured cells showed that phosphorylation of aS at Ser129 contributes to aggregate formation and cell death. Based on these results, we seek to develop therapeutic strategies to prevent neuronal death in PD or DLB, by inhibiting noxious post-translational modification of aS and other pathogenic proteins.