Abstract
The protein alpha-synuclein accumulates in the brain of patients with sporadic Parkinson's disease (PD), and increased gene dosage causes a severe, dominantly inherited form of PD, but we know little about the effects of synuclein that precede degeneration. alpha-Synuclein localizes to the nerve terminal, but the knockout has little if any effect on synaptic transmission. In contrast, we now find that the modest overexpression of alpha-synuclein, in the range predicted for gene multiplication and in the absence of overt toxicity, markedly inhibits neurotransmitter release. The mechanism, elucidated by direct imaging of the synaptic vesicle cycle, involves a specific reduction in size of the synaptic vesicle recycling pool. Ultrastructural analysis demonstrates reduced synaptic vesicle density at the active zone, and imaging further reveals a defect in the reclustering of synaptic vesicles after endocytosis. Increased levels of alpha-synuclein thus produce a specific, physiological defect in synaptic vesicle recycling that precedes detectable neuropathology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / metabolism
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Animals
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Cells, Cultured
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Dopamine / metabolism
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Endocytosis / physiology*
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Exocytosis / physiology
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Mice
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Mice, Transgenic
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Nerve Tissue Proteins / metabolism
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Neurons / cytology
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Neurons / metabolism
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Neurotransmitter Agents / metabolism*
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Parkinson Disease / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Synapsins / metabolism
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Synaptic Transmission / physiology*
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Synaptic Vesicles / metabolism*
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Synaptic Vesicles / ultrastructure
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Vesicular Glutamate Transport Protein 1 / genetics
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Vesicular Glutamate Transport Protein 1 / metabolism
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alpha-Synuclein / genetics
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alpha-Synuclein / metabolism*
Substances
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Adaptor Proteins, Vesicular Transport
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Nerve Tissue Proteins
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Neurotransmitter Agents
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PHluorin
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Recombinant Fusion Proteins
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Synapsins
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Vesicular Glutamate Transport Protein 1
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alpha-Synuclein
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complexin I
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Green Fluorescent Proteins
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Dopamine