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α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

2014; National Academy of Sciences; Volume: 111; Issue: 40 Linguagem: Inglês

10.1073/pnas.1416598111

1091-6490

Jacqueline Burré, Manu Sharma, Thomas C. Südhof,

Alzheimer's disease research and treatments

Significance Physiologically, α-synuclein promotes soluble NSF attachment protein receptor (SNARE) complex assembly during synaptic exocytosis. Pathologically, however, α-synuclein forms neurotoxic aggregates that promote neurodegeneration and represent hallmarks of Parkinson's disease and other synucleinopathies. α-Synuclein exists in a monomeric unfolded state in solution and in an α-helical folded state upon binding to membranes. Yet the relation between these conformational states and their physiological and pathological roles remain unknown. Here, we demonstrate that α-synuclein multimerizes during membrane binding and that the membrane-bound, multimeric form of α-synuclein mediates SNARE complex assembly in presynaptic terminals. Our data delineate a folding pathway for α-synuclein that ranges from a monomeric unfolded form in cytosol to a physiologically functional multimeric form that is membrane bound and chaperones SNARE complex assembly, and that may protect against neurodegeneration.