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

Abstract.

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.