. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010 Sep 24;329(5999):1663-7. PubMed.

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  1. By directly examining SNARE assembly, Burre et al. present good evidence that α-synuclein plays a role in facilitating the assembly of SNARE complexes. They also show that this facilitating process depends on synaptic activity and propose that the physical binding of α-synuclein to VAMP may ultimately mediate the process. However, there were no changes in synaptic transmission in acute brain slices from WT, synuclein overexpressing mice, or mice lacking all synucleins.

    We recently reported that excessive α-synuclein induces a series of pathologic changes including deficits in neurotransmitter release (Scott et al., 2010), in general agreement with a recent study from Robert Edwards's group (Nemani et al., 2010), as well as other reports on cellular and cell-free systems (Larsen et al., 2006; Darios et al., 2010). More recently, we have performed additional electrophysiologic experiments in WT and α-synuclein -/- neurons, in collaboration with Iustin Tabarean, an electrophysiologist at Scripps.

    Though we do not find significant neurotransmitter release deficits in α-synuclein -/- neurons, we consistently see such deficits in neurons overexpressing modest levels of α-synuclein. We cannot comment on the lack of electrophysiologic abnormalities in the α-synuclein overexpressing neurons as seen by Burre et al., but we are pretty sure that in our system, excessive α-synuclein leads to a reduction in neurotransmitter release.

    The authors argue that overexpression (or lack thereof) of α-synuclein does not directly affect neurotransmitter release. However, given the seemingly dramatic effects on SNARE assembly as well as the profound motor/behavioral deficits in the synuclein triple-knockout mice, one question is, then, What is the eventual physiologic defect in the mice described by Burre et al., if not a decrease in neurotransmitter release?

    References:

    . A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010 Jun 16;30(24):8083-95. PubMed.

    . Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010 Jan 14;65(1):66-79. PubMed.

    . Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci. 2006 Nov 15;26(46):11915-22. PubMed.

    . Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci. 2006 Nov 15;26(46):11915-22. PubMed.

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  1. α-Synuclein’s Day Job: To Chaperone SNARE Complexes?