Parkinson's disease (PD) is characterized by the formation of toxic, fibrillar form alpha-synuclein (α-Syn) protein aggregates in dopaminergic neurons. Accumulating evidence has shown a multifactorial interplay between the intracellular calcium elevation and α-Syn dynamics. However, whether membrane depolarization regulates toxic α-Syn aggregates remains unclear. To understand this better, we used an in vitro α-Syn preformed fibrils (PFF) model of PD in human neural cells. We demonstrated functional membrane depolarization in differentiated SH-SY5Y cells induced by two independent treatments: high extracellular K+ and the GABAA receptor blocker picrotoxin. We then observed that these treatments significantly alleviated toxic α-Syn aggregation in PFF-treated SH-SY5Y cells. Moreover, clinically relevant direct current stimulation (DCS) also remarkably decreased toxic α-Syn aggregation in PFF-treated SH-SY5Y cells. Taken together, our findings suggest that membrane depolarization plays an important role in alleviating PFF-induced toxic α-Syn aggregates, and that it may represent a novel therapeutic mechanism for PD.

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Keywords Calcium channel, Direct current stimulation, GABAA receptor, Membrane depolarization, Parkinson’s disease, Preformed fibrils, α-Synuclein
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Journal Molecular brain
Ross, A. (Alysia), Xing, V. (Viktoria), Wang, T.T. (Ting Ting), Bureau, S.C. (Samantha C.), Link, G.A. (Giovana A.), Fortin, T. (Teresa), … Sun, H. (2020). Alleviating toxic α-Synuclein accumulation by membrane depolarization: evidence from an in vitro model of Parkinson's disease. Molecular brain, 13(1). doi:10.1186/s13041-020-00648-8