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

      Science (New York, N.Y.)
      American Association for the Advancement of Science (AAAS)

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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 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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          Journal
          11701929
          10.1126/science.1063522

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