Aggregation of the natively unfolded protein α-synuclein (α-Syn) has been widely correlated to the neuronal death associated with Parkinson’s disease. Mutations and protein overaccumulation can promote the aggregation of α-Syn into oligomers and fibrils. Recent work has suggested that α-Syn oligomers can permeabilize the neuronal membrane, promoting calcium influx and cell death. However, the mechanism of this permeabilization is still uncertain and has yet to be characterized in live cells. This work uses scanning ion conductance microscopy (SICM) to image, in real time and without using chemical probes, the topographies of live SH-SY5Y neuroblastoma cells after exposure to α-Syn oligomers. Substantial morphological changes were observed, with micrometer-scale hills and troughs observed at lower α-Syn concentrations (1.00 μM) and large, transient pores observed at higher α-Syn concentrations (6.0 μM). These findings suggest that α-Syn oligomers may permeabilize the neuronal membrane by destabilizing the lipid bilayer and opening transient pores.

中文翻译：

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α-突触核蛋白寡聚体对活体 SH-SY5Y 神经母细胞瘤细胞膜破坏的实时表征。

天然未折叠蛋白 α-突触核蛋白 (α-Syn) 的聚集与帕金森病相关的神经元死亡广泛相关。突变和蛋白质过度积累可以促进 α-Syn 聚集成寡聚体和原纤维。最近的工作表明，α-Syn 寡聚体可以渗透神经元膜，促进钙内流和细胞死亡。然而，这种透化的机制仍然不确定，还有待在活细胞中进行表征。这项工作使用扫描离子电导显微镜 (SICM) 实时成像，无需使用化学探针，活体 SH-SY5Y 神经母细胞瘤细胞在暴露于 α-Syn 寡聚体后的形貌。观察到了实质性的形态变化，在较低的 α-Syn 浓度 (1.00 μM) 和大、在较高 α-Syn 浓度 (6.0 μM) 下观察到的瞬态孔。这些发现表明，α-Syn 寡聚体可能通过破坏脂质双层和打开瞬时孔来渗透神经元膜。