Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, we observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that the expression of expanded C9orf72 ALS/FTD repeat RNA alone affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival.

多种神经退行性疾病中，包括C9orf72肌萎缩性脊髓侧索硬化症和额颞叶痴呆 (ALS/FTD)中，都报道了核细胞质转运缺陷和特定核孔复合物相关蛋白积累的机制，但机制尚不明确。使用超分辨率结构照明显微镜，我们探索了从C9orf72诱导的多能干细胞源性神经元 (iPSN)分离的细胞核中核孔蛋白发生改变的机制。在评估的 23 种核孔蛋白中，我们观察到 8 种核孔蛋白的子集减少，包括核孔复合物支架的关键成分和跨膜核孔蛋白 POM121。POM121 的减少似乎会引发另外七种核孔蛋白表达的减少，最终影响 Ran GTPase 的定位以及随后在C9orf72 iPSN 中的细胞毒性。总的来说，我们的数据表明，扩展的C9orf72 ALS/FTD 重复 RNA的表达单独影响核 POM121 的表达，影响神经元核内核孔蛋白水平的病理级联的启动，并最终影响下游神经元的存活。