Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct

作者：Kelly A. Conway, Jean‐Christophe Rochet, Robert M. Bieganski, Peter T. Lansbury · 发表于：Science · 年份：2001 · DOI：10.1126/science.1063522 · 被引用次数：1136 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Neurological disorders and treatments、Botulinum Toxin and Related Neurological Disorders

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-synuclein 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-synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the alpha-synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of alpha-synuclein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.