title: Nonaggregated α-synuclein influences SNARE-dependent vesicle docking via membrane binding.
abstract: α-Synuclein (α-Syn), a major component of Lewy body that is considered as the hallmark of Parkinson's disease (PD), has been implicated in neuroexocytosis. Overexpression of α-Syn decreases the neurotransmitter release. However, the mechanism by which α-Syn buildup inhibits the neurotransmitter release is still unclear. Here, we investigated the effect of nonaggregated α-Syn on SNARE-dependent liposome fusion using fluorescence methods. In ensemble in vitro assays, α-Syn reduces lipid mixing mediated by SNAREs. Furthermore, with the more advanced single-vesicle assay that can distinguish vesicle docking from fusion, we found that α-Syn specifically inhibits vesicle docking, without interfering with the fusion. The inhibition in vesicle docking requires α-Syn binding to acidic lipid containing membranes. Thus, these results imply the existence of at least two mechanisms of inhibition of SNARE-dependent membrane fusion: at high concentrations, nonaggregated α-Syn inhibits docking by binding acidic lipids but not v-SNARE; on the other hand, at much lower concentrations, large α-Syn oligomers inhibit via a mechanism that requires v-SNARE interaction [ Choi et al. Proc. Natl. Acad. Sci. U. S. A. 2013 , 110 ( 10 ), 4087 - 4092 ].
authors.affiliation: Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University , Ames, Iowa 50011, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lai
authors.forename: Sunae
authors.initials: S
authors.lastname: Kim
authors.forename: Jobin
authors.initials: J
authors.lastname: Varkey
authors.forename: Xiaochu
authors.initials: X
authors.lastname: Lou
authors.forename: Jae-Kyun
authors.initials: JK
authors.lastname: Song
authors.forename: Jiajie
authors.initials: J
authors.lastname: Diao
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
authors.forename: Yeon-Kyun
authors.initials: YK
authors.lastname: Shin
mesh_terms: D001692:Biological Transport / Q000187:drug effects*; D005089:Exocytosis / Q000187:drug effects; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology*; D008563:Membrane Lipids / Q000378:metabolism; D050600:SNARE Proteins / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000502:physiology*
chemical_list: D008563:Membrane Lipids; D050600:SNARE Proteins; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein