Stress Granule Assembly Disrupts Nucleocytoplasmic Transport.
Stress Granule Assembly Disrupts Nucleocytoplasmic Transport.
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DOI：
10.1016/j.cell.2018.03.025
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发表时间：
2018-05-03
期刊：
影响因子：
64.5
通讯作者：
Lloyd TE
中科院分区：
文献类型：
--
作者：
Zhang K;Daigle JG;Cunningham KM;Coyne AN;Ruan K;Grima JC;Bowen KE;Wadhwa H;Yang P;Rigo F;Taylor JP;Gitler AD;Rothstein JD;Lloyd TE
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，由 C9ORF72 中 GGGGCC 六核苷酸重复扩增介导，是 ALS/FTD 最常见的遗传原因。此外，核细胞质运输破坏也与其他具有蛋白质聚集的神经退行性疾病有关，这表明蛋白质应激破坏核细胞质运输存在共同机制。在这里，我们发现细胞应激通过将关键的核细胞质运输因子定位到应激颗粒、RNA/蛋白质复合物中来破坏核细胞质运输，这些颗粒在 ALS 发病机制中发挥着至关重要的作用。重要的是，抑制应激颗粒组装（例如通过敲低 Ataxin-2）可以抑制核细胞质运输缺陷以及 C9ORF72 介导的 ALS/FTD 中的神经变性。我们的研究结果确定了应激颗粒组装和核细胞质运输之间的联系，这两个基本细胞过程与 C9ORF72-x 介导的 ALS/FTD 和其他神经退行性疾病的发病机制有关。
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-xmediated ALS/FTD and other neurodegenerative diseases.
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影响因子：
14.9
作者：
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通讯作者：
Tarn WY
影响因子：
16.2
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Kim, Hyung-Jun;Raphael, Alya R.;LaDow, Eva S.;McGurk, Leeanne;Weber, Ross A.;Trojanowski, John Q.;Lee, Virginia M-Y;Finkbeiner, Steven;Gitler, Aaron D.;Bonini, Nancy M.
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Bonini, Nancy M.
影响因子：
16.2
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Gasset-Rosa F;Chillon-Marinas C;Goginashvili A;Atwal RS;Artates JW;Tabet R;Wheeler VC;Bang AG;Cleveland DW;Lagier-Tourenne C
通讯作者：
Lagier-Tourenne C
影响因子：
25
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Apicco DJ;Ash PEA;Maziuk B;LeBlang C;Medalla M;Al Abdullatif A;Ferragud A;Botelho E;Ballance HI;Dhawan U;Boudeau S;Cruz AL;Kashy D;Wong A;Goldberg LR;Yazdani N;Zhang C;Ung CY;Tripodis Y;Kanaan NM;Ikezu T;Cottone P;Leszyk J;Li H;Luebke J;Bryant CD;Wolozin B
通讯作者：
Wolozin B