1 research outputs found
Nonaggregated α‑Synuclein Influences SNARE-Dependent Vesicle Docking via Membrane Binding
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]