Stress Granule Assembly Disrupts Nucleocytoplasmic Transport

Ke Zhang, J. Gavin Daigle, Kathleen M. Cunningham, Alyssa N. Coyne, Kai Ruan, Jonathan C. Grima, Kelly E. Bowen, Harsh Wadhwa, Peiguo Yang, Frank Rigo, J. Paul Taylor, Aaron D. Gitler, Jeffrey D. Rothstein, Thomas E. Lloyd

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)958-971.e17
Issue number4
StatePublished - May 3 2018


  • ALS
  • C9ORF72
  • nucleocytoplasmic transport
  • stress granule

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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