Zeroing in on the pathogenic form of α-synuclein and its mechanism of neurotoxicity in Parkinson's disease

被引:368
作者
Volles, MJ
Lansbury, PT
机构
[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Cambridge, MA 02139 USA
[2] Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02139 USA
关键词
D O I
10.1021/bi030086j
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Parkinson's disease (PD) is linked to mutations in the protein alpha-synuclein, which can exist in vitro in several aggregation states, including a natively unfolded monomer, beta-sheet rich oligomer, or protofibril, and a stable amyloid fibril. This work reviews the current literature that is relevant to two linked questions: which of these species is pathogenic, and what is the mechanism of neurotoxicity? The amyloid fibril, fibrillar aggregates, Lewy bodies, and the alpha-synuclein monomer, which is normally expressed at high levels, are all unlikely to be pathogenic, for reasons discussed here. We therefore favor a toxic protofibril scenario, and propose that the pathogenic species is transiently populated during the process of fibrillization. Toxicity may arise from pore-like protofibrils that cause membrane permeabilization. An approach to testing this hypothesis is discussed.
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收藏
页码:7871 / 7878
页数:8
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