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• W2980334468 abstract "Alpha-synuclein (α-syn) is a small presynaptic protein, genetically and neuropathologically linked to a large group of neurodegenerative disorders called synucleinopathies. An understanding of normal α-syn function is likely critical to appreciate the pathologic triggers in disease. Over the years, two seemingly divergent views of α-syn function have emerged. In one, α-syn binds to VAMP2 (synaptobrevin-2) and chaperones SNARE-complexes, but with no effect on neurotransmission. Alternatively, we and others have advocated the concept that α-syn physiologically attenuates neurotransmitter release, by restricting synaptic-vesicle (SV) mobilization and recycling. Here we examined if α-syn/VAMP2 binding regulates α-syn-induced synaptic attenuation, and if the two seemingly divergent views can be reconciled. We identified the precise α-syn amino acid (AA) sequences required for VAMP2 binding by mutagenesis mapping and immunoprecipitation. SV recycling was evaluated in cultured hippocampal neurons using pHluorin assays that report exo/endocytic cycles. Optical single vesicle clustering assays were used to directly visualize effects of α-syn on the clustering of small synaptic-like vesicles in vitro. While full-length α-syn (AA 1-140) interacts with VAMP2 and attenuates SV recycling, an α-syn C-terminal deletion (AA 1-95) lacking the VAMP2-binding domain fails to attenuate SV recycling. Mutagenesis mapping identified ∼9 critical amino acid in α-syn (AA 96-104) required for VAMP2 binding. Perturbation of this α-syn/VAMP2 binding region blocks α-syn-induced synaptic attenuation. In vitro single vesicle clustering experiments show that wild type α-syn induces vesicle-clustering, while perturbation in the α-syn/VAMP2 binding region abrogates this effect. Our data indicate that α-syn/VAMP2 binding is essential for α-syn-induced synaptic attenuation and advocate an “interlocking model” where α-syn multimers on SV surface interact with VAMP2 on adjacent SVs. We propose that these α-syn/VAMP2 interactions help tether synaptic vesicles and maintain physiologic SV clustering." @default.
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• W2980334468 date "2019-07-01" @default.
• W2980334468 modified "2023-09-28" @default.
• W2980334468 title "P4-497: FUNCTIONAL COOPERATION OF α-SYNUCLEIN AND VAMP2 IN SYNAPTIC VESICLE RECYCLING" @default.
• W2980334468 doi "https://doi.org/10.1016/j.jalz.2019.08.043" @default.
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