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Cell. 2018 May 3;173(4):958-971.e17. doi: 10.1016/j.cell.2018.03.025. Epub 2018 Apr 5.

Stress Granule Assembly Disrupts Nucleocytoplasmic Transport.

Author information

1
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.
2
Cellular and Molecular Medicine Program, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
3
Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
4
Brain Science Institute, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
5
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
7
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Department of Genetics, Stanford University, School of Medicine, Stanford, CA 94305, USA.
9
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; Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: jrothstein@jhmi.edu.
10
Department of Neurology, 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; Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: tlloyd4@jhmi.edu.

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.

KEYWORDS:

ALS; C9ORF72; nucleocytoplasmic transport; stress granule

PMID:
29628143
PMCID:
PMC6083872
DOI:
10.1016/j.cell.2018.03.025
[Indexed for MEDLINE]
Free PMC Article

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