Author(s): Fujiwara H; Hasegawa M; Dohmae N; Kawashima A; Masliah E; Goldberg MS; Shen J; Takio K; Iwatsubo T

Title: alpha-Synuclein is phosphorylated in synucleinopathy lesions

Source: NATURE CELL BIOLOGY 4 (2): 160-164

Date: 2002 FEB

Document Type: Journal : Article

DOI: 10.1038/ncb748

Language: English

LCR: 4   CR: 25   LCS: 4   GCS: 404   SCS: 

Comment:  

Address: Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Bunkyo Ku, Tokyo 1130033, Japan.
RIKEN, Characterizat Ctr, Biomol Characterizat Div, Wako, Saitama 3510198, Japan.
Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA.
Harvard Univ, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA.
Brigham & Womens Hosp, Boston, MA 02115 USA.

Reprint: Iwatsubo, T, Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol &
Neurosci, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.

E-mail:  

Author Keywords:  

KeyWords Plus: PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; LEWY BODIES; TAU; FIBRILLIZATION; INCLUSIONS; FILAMENTS

Abstract: The deposition of the abundant presynaptic brain protein alpha-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 synucleinopathies(1,2). Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies(3). However, specific post-translational modifications that underlie the aggregation of alpha-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 alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-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.