Both familial Parkinson's disease mutations accelerate α-synuclein aggregation

被引：637

作者：

Narhi, L ^{[1
]}

Wood, SJ ^{[1
]}

Steavenson, S ^{[1
]}

Jiang, YJ ^{[1
]}

Wu, GM ^{[1
]}

Anafi, D ^{[1
]}

Kaufman, SA ^{[1
]}

Martin, F ^{[1
]}

Sitney, K ^{[1
]}

Denis, P ^{[1
]}

Louis, JC ^{[1
]}

Wypych, J ^{[1
]}

Biere, AL ^{[1
]}

Citron, M ^{[1
]}

机构：

[1] Amgen Inc, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 1999年 / 274卷 / 14期

关键词：

D O I：

10.1074/jbc.274.14.9843

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 a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major component of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD, but their pathogenic mechanism is not understood. Here we show that both wild type and mutant alpha-synuclein form insoluble fibrillar aggregates with antiparallel beta-sheet structure upon incubation at physiological temperature in vitro. Importantly, aggregate formation is accelerated by both PD-linked mutations. Under the experimental conditions, the lag time for the formation of precipitable aggregates is about 280 h for the wild type protein, 180 h for the A30P mutant, and only 100 h for the A53T mutant protein. These data suggest that the formation of alpha-synuclein aggregates could be a critical step in PD pathogenesis, which is accelerated by the PD-linked mutations.

引用

页码：9843 / 9846

页数：4

共 16 条

[1]

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