Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct

被引：948

作者：

Conway, KA ^{[1
]}

Rochet, JC ^{[1
]}

Bieganski, RM ^{[1
]}

Lansbury, PT ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Cambridge, MA 02139 USA

来源：

SCIENCE | 2001年 / 294卷 / 5545期

关键词：

D O I：

10.1126/science.1063522

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：

The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily alpha -synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and alpha -synuctein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to alpha -synuctein and was selective for the protofibril-to-fibril conversion, causing accumulation of the alpha -synuctein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of alpha -synuctein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.

引用

页码：1346 / 1349

页数：4

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