Department of Neuroscience, Carleton University, Ottawa, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Mol Brain. 2020 Jul 31;13(1):108. doi: 10.1186/s13041-020-00648-8.
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 GABA 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.
帕金森病（PD）的特征是多巴胺能神经元中形成毒性、纤维状形式的α-突触核蛋白（α-Syn）蛋白聚集体。越来越多的证据表明，细胞内钙升高和α-Syn 动力学之间存在多种因素的相互作用。然而，膜去极化是否调节毒性α-Syn 聚集体尚不清楚。为了更好地理解这一点，我们使用了人神经细胞中的 PD 体外α-Syn 预形成纤维（PFF）模型。我们通过两种独立的处理方法证实了分化的 SH-SY5Y 细胞中的功能性膜去极化：高细胞外 K 和 GABA 受体阻滞剂胡椒碱。然后我们观察到这些处理方法显著减轻了 PFF 处理的 SH-SY5Y 细胞中有毒的α-Syn 聚集。此外，临床相关的直流刺激（DCS）也显著减少了 PFF 处理的 SH-SY5Y 细胞中有毒的α-Syn 聚集。总之，我们的研究结果表明，膜去极化在减轻 PFF 诱导的毒性α-Syn 聚集体中起重要作用，它可能代表 PD 的一种新的治疗机制。
