Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.
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.
Departments of Neurology and Physiology, Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
Venu M
VM
Nemani
Wei
W
Lu
Victoria
V
Berge
Ken
K
Nakamura
Bibiana
B
Onoa
Michael K
MK
Lee
Farrukh A
FA
Chaudhry
Roger A
RA
Nicoll
Robert H
RH
Edwards
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D005089:Exocytosis / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C485187:PHluorin; D011993:Recombinant Fusion Proteins; D016704:Synapsins; D050598:Vesicular Glutamate Transport Protein 1; D051844:alpha-Synuclein; C095992:complexin I; D049452:Green Fluorescent Proteins; D004298:Dopamine