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

Science  09 Nov 2001:
Vol. 294, Issue 5545, pp. 1346-1349
DOI: 10.1126/science.1063522

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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.

  • * These authors contributed equally to this work.

  • To whom correspondence should be addressed. E-mail: plansbury{at}rics.bwh.harvard.edu

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