Large alpha-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

Abstract

Parkinson disease and dementia with Lewy bodies are featured with the formation of Lewy bodies composed mostly of alpha-synuclein (alpha-Syn) in the brain. Although evidence indicates that the large oligomeric or protofibril forms of alpha-Syn are neurotoxic agents, the detailed mechanisms of the toxic functions of the oligomers remain unclear. Here, we show that large alpha-Syn oligomers efficiently inhibit neuronal SNARE-mediated vesicle lipid mixing. Large alpha-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 alpha-Syn monomer has a negligible effect on lipid mixing even with a 30-fold excess compared with the case of large alpha-Syn oligomers. Thus, the results suggest that large alpha-Syn oligomers function as inhibitors of dopamine release, which thus provides a clue, at the molecular level, to their neurotoxicity.