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

doi:10.1016/j.cell.2018.03.025

Stress Granule Assembly Disrupts Nucleocytoplasmic Transport

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Active Transport, Cell Nucleus / drug effects
Active Transport, Cell Nucleus / physiology*
Aged
Amyotrophic Lateral Sclerosis / metabolism
Amyotrophic Lateral Sclerosis / pathology*
Arsenites / toxicity
Ataxin-2 / antagonists & inhibitors
Ataxin-2 / genetics
Ataxin-2 / metabolism*
C9orf72 Protein / genetics*
C9orf72 Protein / metabolism
DNA Repeat Expansion / genetics
Female
Frontotemporal Dementia / metabolism
Frontotemporal Dementia / pathology*
HEK293 Cells
Humans
Male
Membrane Glycoproteins / metabolism
Middle Aged
Nuclear Pore Complex Proteins / metabolism
Oxidative Stress / drug effects
RNA Interference
RNA, Small Interfering / metabolism
Sodium Compounds / toxicity
alpha Karyopherins / antagonists & inhibitors
alpha Karyopherins / genetics
alpha Karyopherins / metabolism
beta Karyopherins / antagonists & inhibitors
beta Karyopherins / genetics
beta Karyopherins / metabolism
ran GTP-Binding Protein / antagonists & inhibitors
ran GTP-Binding Protein / genetics
ran GTP-Binding Protein / metabolism

Substances

Arsenites
Ataxin-2
C9orf72 Protein
Membrane Glycoproteins
Nuclear Pore Complex Proteins
Nup205 protein, human
POM121 protein, human
RNA, Small Interfering
Sodium Compounds
alpha Karyopherins
beta Karyopherins
sodium arsenite
ran GTP-Binding Protein

Supplementary concepts

Frontotemporal Dementia With Motor Neuron Disease

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding