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Eguchi, Kohgaku; Taoufiq, Zacharie; Thorn-Seshold, Oliver; Trauner, Dirk; Hasegawa, Masato; Takahashi, Tomoyuki (2017): Wild-Type Monomeric alpha-Synuclein Can Impair Vesicle Endocytosis and Synaptic Fidelity via Tubulin Polymerization at the Calyx of Held. In: Journal of Neuroscience, Vol. 37, No. 25: pp. 6043-6052
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alpha-Synuclein is a presynaptic protein the function of which has yet to be identified, but its neuronal content increases in patients of synucleinopathies including Parkinson's disease. Chronic overexpression of alpha-synuclein reportedly expresses various phenotypes of synaptic dysfunction, but the primary target of its toxicity has not been determined. To investigate this, we acutely loaded human recombinant alpha-synuclein or its pathological mutants in their monomeric forms into the calyces of Held presynaptic terminals in slices from auditorily mature and immature rats of either sex. Membrane capacitance measurements revealed significant and specific inhibitory effects of WT monomeric alpha-synuclein on vesicle endocytosis throughout development. However, the alpha-synuclein A53T mutant affected vesicle endocytosis only at immature calyces, whereas theA30P mutant had no effect throughout. TheendocyticimpairmentbyWT alpha-synuclein was rescued by intraterminal coloading of the microtubule (MT) polymerization blocker nocodazole. Furthermore, it was reversibly rescued by presynaptically loaded photostatin-1, a photoswitcheable inhibitor of MT polymerization, in a light-wavelength-dependent manner. In contrast, endocytic inhibition by the A53T mutant at immature calyces was not rescued by nocodazole. Functionally, presynaptically loaded WT alpha-synuclein had no effect on basal synaptic transmission evoked at a low frequency, but significantly attenuated exocytosis and impaired the fidelity of neurotransmission during prolonged high-frequency stimulation. We conclude thatmonomericWT alpha-synuclein primarily inhibits vesicle endocytosis via MT overassembly, thereby impairing high-frequency neurotransmission.