Wild-type monomeric α-synuclein can impair vesicle endocytosis and synaptic fidelity via tubulin polymerization at the calyx of held Journal Article

Author(s): Eguchi, Kohgaku; Taoufiq, Zachari; Thorn Seshold, Oliver; Trauner, Dirk; Hasegawa, Masato; Takahashi, Tomoyuki
Article Title: Wild-type monomeric α-synuclein can impair vesicle endocytosis and synaptic fidelity via tubulin polymerization at the calyx of held
Affiliation IST Austria
Abstract: α-Synuclein is a presynaptic protein the function of which has yet to be identified, but its neuronal content increases in patients of synucleinopa-thies including Parkinson’s disease. Chronic overexpression of α-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 α-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 α-synuclein on vesicle endocytosis throughout development. However, the α-synuclein A53T mutant affected vesicle endocytosis only at immature calyces, where as the A30P mutant had no effect throughout. The endocytic impairment by WTα-synuclein was rescued by intraterminal coloading of the microtubule (MT) polymerization blocker nocodazole. Furthermore, it was reversibly rescued by presynaptically loaded photostatin-1, a pho-toswitcheable inhibitor of MT polymerization, inalight-wavelength-dependent manner. Incontrast, endocyticinhibition by the A53T mutant at immature calyces was not rescued by nocodazole. Functionally, presynaptically loaded WT α-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 that monomeric WTα-synuclein primarily inhibits vesicle endocytosis via MT overassembly, thereby impairing high-frequency neurotransmission.
Keywords: Synaptic Transmission; Microtubules; Calyx of held; Alpha-synuclein; vesicle endocytosis
Journal Title: European Journal of Neuroscience
Volume: 37
Issue 25
ISSN: 1460-9568
Publisher: Wiley  
Date Published: 2017-06-21
Start Page: 6043
End Page: 6052
DOI: 10.1523/JNEUROSCI.0179-17.2017
Notes: This work was supported by the Okinawa Institute of Science and Technology, the Core Research for Evolutionary Scienceand Technology of the Japan Science and Technology Agency (T.T.), and the Japan Society for the Promotion of Science (Grant-in-Aid for Young Scientists to K.E.). We thank Yasuo Ihara and Takeshi Sakaba for comments and Steven Aird for editing this manuscript.
Open access: no