Nonaggregated 伪-Synuclein Influences SNARE-Dependent Vesicle Docking via Membrane Binding

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• 作者：Ying Lai ; Sunae Kim ; Jobin Varkey ; Xiaochu Lou ; Jae-Kyun Song ; Jiajie Diao ; Ralf Langen ; Yeon-Kyun Shin
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：June 24, 2014
• 年：2014
• 卷：53
• 期：24
• 页码：3889-3896
• 全文大小：476K
• ISSN：1520-4995

文摘

伪-Synuclein (伪-Syn), a major component of Lewy body that is considered as the hallmark of Parkinson鈥檚 disease (PD), has been implicated in neuroexocytosis. Overexpression of 伪-Syn decreases the neurotransmitter release. However, the mechanism by which 伪-Syn buildup inhibits the neurotransmitter release is still unclear. Here, we investigated the effect of nonaggregated 伪-Syn on SNARE-dependent liposome fusion using fluorescence methods. In ensemble in vitro assays, 伪-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 伪-Syn specifically inhibits vesicle docking, without interfering with the fusion. The inhibition in vesicle docking requires 伪-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 伪-Syn inhibits docking by binding acidic lipids but not v-SNARE; on the other hand, at much lower concentrations, large 伪-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鈭?092].