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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antioxidants / pharmacology
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Biopolymers / chemistry
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Biopolymers / metabolism
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Catecholamines / pharmacology
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Cytoplasm / metabolism
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Dopamine / chemistry
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Dopamine / metabolism*
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Dopamine / pharmacology
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Humans
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Levodopa / pharmacology
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Nerve Tissue Proteins / chemistry*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / isolation & purification
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Nerve Tissue Proteins / metabolism*
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Oxidation-Reduction
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Oxidative Stress
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Parkinson Disease / etiology
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Parkinson Disease / metabolism
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Parkinson Disease / therapy
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Quinones / metabolism
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Spectrometry, Fluorescence
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Synaptic Vesicles / metabolism
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Synucleins
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alpha-Synuclein
Substances
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Antioxidants
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Biopolymers
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Catecholamines
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Nerve Tissue Proteins
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Quinones
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SNCA protein, human
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Synucleins
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alpha-Synuclein
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Levodopa
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Dopamine