Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and nucleocytoplasmic transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.

中文翻译：

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应力颗粒大会打乱了核质运输。

核细胞质运输中的缺陷已被确定为肌萎缩性侧索硬化（ALS）和额颞叶痴呆（FTD）中由GGGGCC六核苷酸在C9ORF72中重复扩增介导的关键病因，这是ALS / FTD的最常见遗传原因。此外，胞浆运输破坏也已经被认为与其他具有蛋白质聚集的神经退行性疾病有关，这暗示了蛋白质应激破坏胞浆运输的共同机制。在这里，我们显示细胞应激通过将关键的核质转运因子定位到应激颗粒，在ALS发病机理中起关键作用的RNA /蛋白质复合体，破坏了核质转运。重要的是，例如通过敲低Ataxin-2来抑制应力颗粒的组装，抑制C9ORF72介导的ALS / FTD中的核质运输缺陷以及神经退行性变。我们的发现确定了应力颗粒组装与核质运输之间的联系，这两个基本的细胞过程与C9ORF72介导的ALS / FTD的发病机理及其他神经退行性疾病有关。