Nonaggregated α-Synuclein Influences SNARE-Dependent Vesicle Docking via Membrane Binding
- Nonaggregated α-Synuclein Influences SNARE-Dependent Vesicle Docking via Membrane Binding
- Ying Lai; Sunae Kim; Jobin Varkey; Xiaochu Lou; Jae-Kyun Song; Jiajie Diao; Ralf Langen; 신년균
- α-Synuclein; Vesicle docking; SNARE
- Issue Date
- VOL 53, NO 24, 3889-3896
- 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].
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