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J Neurol. 2003 Oct;250 Suppl 3:III11-4.

Aggregation of alpha-synuclein in the pathogenesis of Parkinson's disease.

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Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyoku, 113-0033, Tokyo, Japan. iwatsubo@mol.


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 alpha-synuclein is one of the major components of LBs. Thus, the deposition of alpha-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 alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific post-translational modifications that characterize and underlie the aggregation of alpha-synuclein in synucleinopathy brains by mass spectrometry and using a s pecific antibody,and found that serine 129 of alpha-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.

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