Sci. Aging Knowl. Environ., 14 November 2001
Kinetic Stabilization of the -Synuclein Protofibril by a Dopamine--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 -synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and -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 -synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the -synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of -synuclein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.
Science of Aging Knowledge Environment. ISSN 1539-6150