Kinetic Stabilization of the {alpha}-Synuclein Protofibril by a Dopamine-{alpha}-Synuclein Adduct

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Sci. Aging Knowl. Environ., 14 November 2001
Vol. 2001, Issue 7, p. or22

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Kinetic Stabilization of the ${alpha}$ -Synuclein Protofibril by a Dopamine- ${alpha}$ -Synuclein Adduct

Kelly A. Conway, Jean-Christophe Rochet, Robert M. Bieganski, and Peter T. Lansbury Jr.

http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/7/or22

Abstract: Science 294, 1346 (2001).

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.