Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we provide evidence that CHMP7, a critical mediator of NPC quality control, is increased in nuclei of C9orf72 and sporadic ALS induced pluripotent stem cell (iPSC)–derived spinal neurons (iPSNs) and postmortem human motor cortex before the emergence of Nup alterations. Inhibiting the nuclear export of CHMP7 triggered Nup reduction and TDP-43 dysfunction and pathology in human neurons. Knockdown of CHMP7 alleviated disease-associated Nup alterations, deficits in Ran GTPase localization, defects in TDP-43–associated mRNA expression, and downstream glutamate-induced neuronal death. Thus, our data support a role for altered CHMP7-mediated Nup homeostasis as a prominent initiating pathological mechanism for familial and sporadic ALS and highlight the potential for CHMP7 as therapeutic target.

核孔复合体 (NPC) 的成分 [核孔蛋白 (Nups)] 和功能的改变被认为是神经变性遗传形式的发病机制的贡献者，包括 C9orf72 肌萎缩侧索硬化症/额颞叶痴呆 (ALS/FTD )。我们假设 Nup 改变和随之而来的 NPC 功能丧失可能位于 ALS、FTD 和相关神经退行性疾病中广泛观察到的 TDP-43 功能障碍和错误定位的上游。在这里，我们提供的证据表明，在 Nup 改变出现之前， CHMP7（NPC 质量控制的关键介质）在C9orf72和散发性 ALS 诱导的多能干细胞 (iPSC) 衍生的脊髓神经元 (iPSN) 和死后人类运动皮层的细胞核中增加。抑制 CHMP7 的核输出会引发人类神经元中 Nup 的减少和 TDP-43 的功能障碍和病理学。CHMP7 的敲除减轻了疾病相关的 Nup 改变、Ran GTPase 定位缺陷、TDP-43 相关 mRNA 表达缺陷以及下游谷氨酸诱导的神经元死亡。因此，我们的数据支持 CHMP7 介导的 Nup 稳态改变作为家族性和散发性 ALS 的重要起始病理机制，并强调了 CHMP7 作为治疗靶点的潜力。