Large α-Synuclein Oligomers Inhibit Neuronal SNARE-Mediated Vesicle Docking
- Large α-Synuclein Oligomers Inhibit Neuronal SNARE-Mediated Vesicle Docking
- 최봉규; 최말기; 김재열; 양유수; Ying Lai; 권대혁; 이남기; 신년균
- exocytosis; neuroscience; vesicle fusion; alternating-laser excitation; single-vesicle
- Issue Date
- Proceedings of the National Academy of Sciences of the United States of America
- VOL 110, NO 10, 4087-4092
- Parkinson disease and dementia with Lewy bodies are featured with the formation of Lewy bodies composed mostly of α-synuclein (α-Syn) in the brain. Although evidence indicates that the large oligomeric or protofibril forms of α-Syn are neurotoxic agents, the detailed mechanisms of the toxic functions of the oligomers remain unclear. Here, we show that large α-Syn oligomers efficiently inhibit neuronal SNARE-mediated vesicle lipid mixing. Large α-Syn oligomers preferentially bind to the N-terminal domain of a vesicular SNARE protein, synaptobrevin-2, which blocks SNARE-mediated lipid mixing by preventing SNARE complex formation. In sharp contrast, the α-Syn monomer has a negligible effect on lipid mixing even with a 30-fold excess compared with the case of large α-Syn oligomers. Thus, the results suggest that large α-Syn oligomers function as inhibitors of dopamine release, which thus provides a clue, at the molecular level, to their neurotoxicity.
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