Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers

The primary hallmark of Parkinson's disease (PD) is the generation of Lewy bodies of which major component is alpha -synuclein (alpha -Syn). Because of increasing evidence of the fundamental roles of alpha -Syn oligomers in disease progression, alpha -Syn oligomers have become potential targets for therapeutic interventions for PD. One of the potential toxicities of alpha -Syn oligomers is their inhibition of SNARE-mediated vesicle fusion by specifically interacting with vesicle-SNARE protein synaptobrevin-2 (Syb2), which hampers dopamine release. Here, we show that alpha -Syn monomers and oligomers cooperatively inhibit neuronal SNARE-mediated vesicle fusion. alpha -Syn monomers at submicromolar concentrations increase the fusion inhibition by alpha -Syn oligomers. This cooperative pathological effect stems from the synergically enhanced vesicle clustering. Based on this cooperative inhibition mechanism, we reverse the fusion inhibitory effect of alpha -Syn oligomers using small peptide fragments. The small peptide fragments, derivatives of alpha -Syn, block the binding of alpha -Syn oligomers to Syb2 and dramatically reverse the toxicity of alpha -Syn oligomers in vesicle fusion. Our findings demonstrate a new strategy for therapeutic intervention in PD and related diseases based on this specific interaction of alpha -Syn.