Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis

Neuron. 2010 Jan 14;65(1):66-79. doi: 10.1016/j.neuron.2009.12.023.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Cells, Cultured
  • Dopamine / metabolism
  • Endocytosis / physiology*
  • Exocytosis / physiology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Neurotransmitter Agents / metabolism*
  • Parkinson Disease / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Synapsins / metabolism
  • Synaptic Transmission / physiology*
  • Synaptic Vesicles / metabolism*
  • Synaptic Vesicles / ultrastructure
  • Vesicular Glutamate Transport Protein 1 / genetics
  • Vesicular Glutamate Transport Protein 1 / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • Adaptor Proteins, Vesicular Transport
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • PHluorin
  • Recombinant Fusion Proteins
  • Synapsins
  • Vesicular Glutamate Transport Protein 1
  • alpha-Synuclein
  • complexin I
  • Green Fluorescent Proteins
  • Dopamine