1. Neuroscience

Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS

  1. Janani Parameswaran
  2. Nancy Zhang
  3. Elke Braems
  4. Kedamawit Tilahun
  5. Devesh C Pant
  6. Keena Yin
  7. Seneshaw Asress
  8. Kara Heeren
  9. Anwesha Banerjee
  10. Emma Davis
  11. Samantha L Schwartz
  12. Graeme L Conn
  13. Gary J Bassell
  14. Ludo Van Den Bosch
  15. Jie Jiang  Is a corresponding author
  1. Emory University, United States
  2. KU Leuven, Belgium
https://doi.org/10.7554/eLife.85902
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Cite this article
  1. Janani Parameswaran
  2. Nancy Zhang
  3. Elke Braems
  4. Kedamawit Tilahun
  5. Devesh C Pant
  6. Keena Yin
  7. Seneshaw Asress
  8. Kara Heeren
  9. Anwesha Banerjee
  10. Emma Davis
  11. Samantha L Schwartz
  12. Graeme L Conn
  13. Gary J Bassell
  14. Ludo Van Den Bosch
  15. Jie Jiang
(2023)
Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
eLife 12:e85902.
https://doi.org/10.7554/eLife.85902
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Abstract

GGGGCC (G4C2) hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C4G2) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9ORF72 antisense C4G2 repeat expanded RNAs trigger the activation of the PKR/eIF2α-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG initiated translation, leading to global translation inhibition and stress granule formation. Reducing PKR levels with either siRNA or morpholinos mitigates integrated stress response and toxicity caused by the antisense C4G2 RNAs in cell lines, primary neurons, and zebrafish. Increased phosphorylation of PKR/eIF2α is also observed in the frontal cortex of C9ORF72 FTD/ALS patients. Finally, only antisense C4G2, but not sense G4C2, repeat expanded RNAs robustly activate the PKR/eIF2α pathway and induce aberrant stress granule formation. These results provide a mechanism by which antisense C4G2 repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9ORF72 repeat expansions.

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All data generated or analysed during this study are included in the manuscript.

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Author details

  1. Janani Parameswaran

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9030-4953

  2. Nancy Zhang

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Elke Braems

    Department of Neurosciences, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  4. Kedamawit Tilahun

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2107-1580

  5. Devesh C Pant

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4046-4195

  6. Keena Yin

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Seneshaw Asress

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Kara Heeren

    Department of Neurosciences, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  9. Anwesha Banerjee

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Emma Davis

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Samantha L Schwartz

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Graeme L Conn

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. Gary J Bassell

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  14. Ludo Van Den Bosch

    Department of Neurosciences, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  15. Jie Jiang

    Department of Cell Biology, Emory University, Atlanta, United States
    For correspondence
    jie.jiang@emory.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9519-4992

Funding

National Institute of Neurological Disorders and Stroke (R01NS114253)

  • Anwesha Banerjee
  • Gary J Bassell

National Institutes of Health (R01AG068247)

  • Jie Jiang

ALS Association (21-PDF-585)

  • Janani Parameswaran

Fonds Wetenschappelijk Onderzoek (G0C1620N)

  • Ludo Van Den Bosch

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Parameswaran et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Janani Parameswaran
  2. Nancy Zhang
  3. Elke Braems
  4. Kedamawit Tilahun
  5. Devesh C Pant
  6. Keena Yin
  7. Seneshaw Asress
  8. Kara Heeren
  9. Anwesha Banerjee
  10. Emma Davis
  11. Samantha L Schwartz
  12. Graeme L Conn
  13. Gary J Bassell
  14. Ludo Van Den Bosch
  15. Jie Jiang
(2023)
Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS
eLife 12:e85902.
https://doi.org/10.7554/eLife.85902

Share this article

https://doi.org/10.7554/eLife.85902

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