α-synuclein is phosphorylated in synucleinopathy lesions

Abstract

The deposition of the abundant presynaptic brain protein α-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies1,2. Importantly, the identification of missense mutations in the α-synuclein gene in some pedigrees of familial PD has strongly implicated α-synuclein in the pathogenesis of PD and other synucleinopathies3. However, specific post-translational modifications that underlie the aggregation of α-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of α-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of α-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders. © 2002 Nature Publishing Group.