Ever since mutations in the gene for αsynuclein were found to cause some cases of familial Parkinson's disease, scientists have scrambled to figure out exactly what is the function of this protein (see related news item and item). A report in the October 15 Journal of Neuroscience further supports the theory that α-synuclein is somehow involved in maintaining pools of synaptic neurotransmitters.

Over the last few years, evidence has grown for the protein's association with synaptic vesicles, subcellular compartments that corral dopamine and other chemical transmitters at nerve terminals. Robert Nussbaum and colleagues at the National Institutes of Health in Bethesda, MD, Baylor College of Medicine in Houston, Texas, and Primal Inc. in Seattle, Washington, used mouse knockouts of αsynuclein to show that it plays a crucial role in the maintenance of a subset of these vesicles.

Joint authors Deborah Cabin and Kazuhiro Shimazu used electron microscopy to examine neurons of the hippocampus. They found that these neurons were strikingly devoid of undocked vesicles-those that are not in contact with the synaptic membrane and are, therefore, more than one stimulus away from fusing with it and releasing their contents. The authors observed similar losses in neurons cultured from the knockout mice. In contrast, the numbers of docked vesicles-those poised for fusion and release-were similar in knockouts and controls.

The authors found that loss of αsynuclein compromised synaptic transmission only in one respect. When a neuron is subjected to a prolonged barrage of stimuli that depletes docked vesicles, it usually sends in the reserves, or undocked vesicles, to pick up the slack. This mobilization was much weaker in the knockout animals, as evident by electrophysiological measurements.

Curiously, these microscopic and electrophysiological results are at odds with previous characterizations of α-synuclein knockouts (Abeliovich et al., 2000). They are, however, in agreement with those of Murphy et al., who used antisense oligonucleotides to ablate α-synuclein and the number of pre-synaptic vesicles. In that study, however, the authors found that other synaptic proteins were also affected, whereas Cabin et al. observed no changes in levels of key synaptic players including synapsin-1 and synaptophysin.—Tom Fagan

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References

News Citations

  1. A Role for a Synuclein Protein
  2. α-Synuclein Appears to Regulate Synaptic Vesicles

Paper Citations

  1. . Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000 Jan;25(1):239-52. PubMed.
  2. . Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000 May 1;20(9):3214-20. PubMed.

Further Reading

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Primary Papers

  1. . Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci. 2002 Oct 15;22(20):8797-807. PubMed.