Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Brain Science Institute, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Cell. 2018 May 3;173(4):958-971.e17. doi: 10.1016/j.cell.2018.03.025. Epub 2018 Apr 5.
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.
核质转运缺陷已被确定为肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的关键致病事件，其由 C9ORF72 中 GGGGCC 六核苷酸重复扩展介导，这是 ALS/FTD 的最常见遗传原因。此外，核质转运中断也与其他具有蛋白质聚集的神经退行性疾病有关，表明蛋白质应激破坏核质转运的机制相似。在这里，我们表明细胞应激通过将关键的核质转运因子定位到应激颗粒中来破坏核质转运，应激颗粒是在 ALS 发病机制中起关键作用的 RNA/蛋白质复合物。重要的是，抑制应激颗粒组装，例如通过敲低 Ataxin-2，可以抑制核质转运缺陷以及 C9ORF72 介导的 ALS/FTD 中的神经退行性变。我们的发现确定了应激颗粒组装与核质转运之间的联系，这两个基本的细胞过程都与 C9ORF72 介导的 ALS/FTD 和其他神经退行性疾病的发病机制有关。
