Aggregation of alpha-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 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.
Iwatsubo
Takeshi
T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyoku, 113-0033, Tokyo, Japan. iwatsubo@mol. f.u-tokyo.ac.jp
D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000737:chemistry* / Q000276:immunology / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D012694:Serine / Q000737:chemistry; D051843:Synucleins; D051844:alpha-Synuclein
D000911:Antibodies, Monoclonal; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D012694:Serine