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    Science. 2001 Nov 9;294(5545):1346-9.

    Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct.

    Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr.

    Source

    Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.

    Abstract

    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.

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    PMID:
    11701929
    [PubMed - indexed for MEDLINE]

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