Abstract
The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54 83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.
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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14-3-3 Proteins
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Apoptosis
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Cells, Cultured
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Dopamine / physiology*
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Humans
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Nerve Degeneration / pathology
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Nerve Degeneration / physiopathology*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Neurons / cytology
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Neurons / physiology*
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Neuroprotective Agents / pharmacology*
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Neurotoxins / toxicity*
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Parkinson Disease / pathology
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Parkinson Disease / physiopathology*
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Phosphoproteins / genetics
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Phosphoproteins / physiology
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Substantia Nigra / pathology
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Synucleins
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Transfection
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Tumor Cells, Cultured
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Tyrosine 3-Monooxygenase / physiology
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alpha-Synuclein
Substances
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14-3-3 Proteins
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Nerve Tissue Proteins
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Neuroprotective Agents
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Neurotoxins
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Phosphoproteins
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SNCA protein, human
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Synucleins
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alpha-Synuclein
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Tyrosine 3-Monooxygenase
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Dopamine