Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations

被引：376
作者：
Li, WX
West, N
Colla, E
Pletnikova, O
Troncoso, JC
Marsh, L
Dawson, TM
Jäkälä, P
Hartmann, T
Price, DL
Lee, MK
机构：
[1] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA
[5] Johns Hopkins Univ, Sch Med, Udall Parkinsons Dis Res Ctr, Baltimore, MD 21205 USA
[6] Kuopio Univ Hosp, Dept Neurol, FIN-70211 Kuopio, Finland
[7] Heidelberg Univ, Ctr Mol Biol, D-69120 Heidelberg, Germany
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2005年 / 102卷 / 06期
关键词：
alpha-synucleinopathy; mass spectrometry; proteolysis; Lewy body;
D O I：
10.1073/pnas.0406976102
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Abnormal biology of alpha-synuclein (alpha-Syn) is directly implicated in the pathogenesis of Parkinson's disease and other alpha-synucleinopathies. Herein, we demonstrate that C-terminally truncated alpha-Syn (alpha-SynDeltaC), enriched in the pathological alpha-Syn aggregates, is normally generated from full-length alpha-Syn independent of alpha-Syn aggregation in brains and in cultured cells. The accumulation of alpha-SynAC is enhanced in neuronal cells as compared with non-neuronal cells. Significantly, the expression of familial Parkinson's disease-linked mutant alpha-Syn is associated with the enhanced cellular accumulation of alpha-SynAC. Moreover, substoichiometric amounts of alpha-SynAC enhance the in vitro aggregation of the more abundant full-length alpha-Syn. Finally, cases of alpha-synucleinopathy exhibit increases in the total soluble alpha-Syn and a higher proportion of soluble alpha-SynAC, a condition favoring the aggregation of alpha-Syn. Collectively, our results indicate that the biology behind the generation and accumulation of alpha-SynAC is likely to have relevance for the initiation and the progression of alpha-Syn aggregation in vivo.
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页码：2162 / 2167
页数：6
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