Increased Expression of α-Synuclein Reduces Neurotransmitter Release by Inhibiting Synaptic Vesicle Reclustering after Endocytosis

Venu M. Nemani, Wei Lu, Victoria Berge, Ken Nakamura, Bibiana Onoa, Michael K. Lee, Farrukh A. Chaudhry, Roger A. Nicoll, Robert H. Edwards

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637 Scopus citations

Abstract

The protein α-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. α-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 α-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 α-synuclein thus produce a specific, physiological defect in synaptic vesicle recycling that precedes detectable neuropathology.

Original languageEnglish (US)
Pages (from-to)66-79
Number of pages14
JournalNeuron
Volume65
Issue number1
DOIs
StatePublished - Jan 14 2010

Bibliographical note

Funding Information:
We thank E. Wallender and B. Mukherjee for technical support, K. Thorn and the UCSF Nikon Center for assistance with the imaging, M. Larsson for help with the electron microscopy, A. Frigessi for guidance in the statistical analysis, and R. Tsien for thoughtful suggestions. This work was supported by the UCSF MSTP and a predoctoral fellowship from the Hillblom Foundation (to V.M.N.), a postdoctoral fellowship from the Hillblom Foundation and a Burroughs-Wellcome Medical Scientist Fund Career Award (to K.N.), the American Heart Association (W.L.), the University of Oslo (V.B.), the Norwegian Research Council (F.A.C.), the National Institutes of Mental Health (R.A.N. and R.H.E.), the National Parkinson Foundation, and the Michael J. Fox Foundation (R.H.E.).

Keywords

  • cellbio
  • molneuro

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