@article{76ab63b46c3648acacb2276ec818f9b1,
title = "Stress Granule Assembly Disrupts Nucleocytoplasmic Transport",
abstract = "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. Sequestration of key nucleocytoplasmic transport factors in stress granules exacerbates neurodegeneration, and blocking this aspect of the stress response ameliorates effects in a model of C9-ALS/FTD.",
keywords = "ALS, C9ORF72, nucleocytoplasmic transport, stress granule",
author = "Ke Zhang and Daigle, {J. Gavin} and Cunningham, {Kathleen M.} and Coyne, {Alyssa N.} and Kai Ruan and Grima, {Jonathan C.} and Bowen, {Kelly E.} and Harsh Wadhwa and Peiguo Yang and Frank Rigo and Taylor, {J. Paul} and Gitler, {Aaron D.} and Rothstein, {Jeffrey D.} and Lloyd, {Thomas E.}",
note = "Funding Information: We thank Xiaopei Tang, Weibo Zhou, and Lin Xue for their technical support, Joshua Wheeler for insightful discussions, and the following individuals for various constructs: Mark Hipp (S-GFP construct), Yuh Min Chook (MBP-M9M and MBP constructs), James Shorter (GFP-Importin β2 constructs), Xinmei Wen, and Davide Trotti (dipeptide repeat proteins constructs). KPT-350 is from Karyopharm Therapeutics. We thank Adrian Isaacs, Kim McKim, and the Bloomington Drosophila Stock Center for fly stocks. K.Z. is a recipient of Milton Safenowitz Postdoctoral Fellowship ( ALSA ). K.M.C. ( NS100401 ) and J.C.G. ( NS103360 ) are recipients of F31 NRSA Awards. J.C.G is a recipient of NSF GRFP (2014178388) , Thomas Shortman , and Axol Science Scholarships. J.D.R. is supported by NIH ( R01NS085207 , R01NS099320 , P01NS09911 , R01NS094239 , U24NS078736 ), Target ALS , Muscular Dystrophy Association , ALS Association , Answer ALS , and The Robert Packard Center for ALS Research . T.E.L. is supported by NIH ( R01NS082563 , NS094239 , P30NS050274 ), ALSA , Target ALS , and the Robert Packard Center for ALS . Funding Information: We thank Xiaopei Tang, Weibo Zhou, and Lin Xue for their technical support, Joshua Wheeler for insightful discussions, and the following individuals for various constructs: Mark Hipp (S-GFP construct), Yuh Min Chook (MBP-M9M and MBP constructs), James Shorter (GFP-Importin ?2 constructs), Xinmei Wen, and Davide Trotti (dipeptide repeat proteins constructs). KPT-350 is from Karyopharm Therapeutics. We thank Adrian Isaacs, Kim McKim, and the Bloomington Drosophila Stock Center for fly stocks. K.Z. is a recipient of Milton Safenowitz Postdoctoral Fellowship (ALSA). K.M.C. (NS100401) and J.C.G. (NS103360) are recipients of F31 NRSA Awards. J.C.G is a recipient of NSF GRFP (2014178388), Thomas Shortman, and Axol Science Scholarships. J.D.R. is supported by NIH (R01NS085207, R01NS099320, P01NS09911, R01NS094239, U24NS078736), Target ALS, Muscular Dystrophy Association, ALS Association, Answer ALS, and The Robert Packard Center for ALS Research. T.E.L. is supported by NIH (R01NS082563, NS094239, P30NS050274), ALSA, Target ALS, and the Robert Packard Center for ALS. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = may,
day = "3",
doi = "10.1016/j.cell.2018.03.025",
language = "English (US)",
volume = "173",
pages = "958--971.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}