Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct
Top Cited Papers
- 9 November 2001
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 294 (5545) , 1346-1349
- https://doi.org/10.1126/science.1063522
Abstract
The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily α-synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and α-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 α-synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the α-synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of α-synuclein–associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.Keywords
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