title: Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2.
abstract: α-Synuclein is a presynaptic protein that is implicated in Parkinson's and other neurodegenerative diseases. Physiologically, native α-synuclein promotes presynaptic SNARE-complex assembly, but its molecular mechanism of action remains unknown. Here, we found that native α-synuclein promotes clustering of synaptic-vesicle mimics, using a single-vesicle optical microscopy system. This vesicle-clustering activity was observed for both recombinant and native α-synuclein purified from mouse brain. Clustering was dependent on specific interactions of native α-synuclein with both synaptobrevin-2/VAMP2 and anionic lipids. Out of the three familial Parkinson's disease-related point mutants of α-synuclein, only the lipid-binding deficient mutation A30P disrupted clustering, hinting at a possible loss of function phenotype for this mutant. α-Synuclein had little effect on Ca(2+)-triggered fusion in our reconstituted single-vesicle system, consistent with in vivo data. α-Synuclein may therefore lead to accumulation of synaptic vesicles at the active zone, providing a 'buffer' of synaptic vesicles, without affecting neurotransmitter release itself. DOI:http://dx.doi.org/10.7554/eLife.00592.001.
authors: Department of Molecular and Cellular Physiology , Stanford University , Stanford , United States ; Department of Structural Biology , Stanford University , Stanford , United States ; Departments of Photon Sciences, and Neurology and Neurological Sciences , Stanford University , Stanford , United States ; Howard Hughes Medical Institute, Stanford University , Stanford , United States.
authors: Jiajie
authors: J
authors: Diao
authors: Jacqueline
authors: J
authors: Burré
authors: Sandro
authors: S
authors: Vivona
authors: Daniel J
authors: DJ
authors: Cipriano
authors: Manu
authors: M
authors: Sharma
authors: Minjoung
authors: M
authors: Kyoung
authors: Thomas C
authors: TC
authors: Südhof
authors: Axel T
authors: AT
authors: Brunger
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000302:isolation & purification; D000818:Animals; D001921:Brain / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000302:isolation & purification; D010743:Phospholipids / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism*; D050863:Synaptotagmin I / Q000235:genetics / Q000302:isolation & purification; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism*; D051844:alpha-Synuclein / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D050863:Synaptotagmin I; C494311:Syt1 protein, mouse; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein; C095992:complexin I
keywords: Mouse; Parkinson's disease; alpha-synuclein; synaptic terminals
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