Aggregation of α-synuclein in the pathogenesis of Parkinson’s disease

Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). By raising a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immuola-beled LBs, we found that α-synuclein is one of the major components of LBs. Thus, the deposition of α-synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells,was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in α-synuclein gene in some pedigrees of familial PD has strongly implicated α-synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific post-translational modifications that characterize and underlie the aggregation of α-synuclein in synucleinopathy brains by mass spectrometry and using a s pecific antibody,and found that serine 129 of α-synuclein deposited in synucleinopathy lesions is selectively and extensively phosphorylated. These findings underscore the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.