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Science 9 November 2001:
Vol. 294. no. 5545, pp. 1346 - 1349
DOI: 10.1126/science.1063522
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Reports

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

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

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.

Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
*   These authors contributed equally to this work.

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

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