Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct
Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct
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DOI：
10.1126/science.1063522
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发表时间：
2001-11-09
期刊：
影响因子：
56.9
通讯作者：
Lansbury, PT
中科院分区：
文献类型：
--
作者：
Conway, KA;Rochet, JC;Lansbury, PT
帕金森病（PD）中的黑质缺乏多巴胺能神经元，并且含有主要包含α-突触核蛋白的纤维状路易体。我们筛选了一个文库来鉴定药物样分子，以探测神经变性和α-突触蛋白原纤维化之间的关系。15种原纤维抑制剂中除一种外均为与多巴胺相关的儿茶酚胺。多巴胺的抑制活性依赖于其与α-synuctein的氧化连接，并且对原纤维到原纤维的转化具有选择性，导致α-synuctein原纤维的积累。加合物的形成为PD中α-突触蛋白相关神经毒性的多巴胺能选择性提供了解释，并对当前和未来的PD治疗和诊断策略具有意义。
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.