Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

  1. Magda Luciana Atilano
  2. Sebastian Grönke
  3. Teresa Niccoli
  4. Liam Kempthorne
  5. Oliver Hahn
  6. Javier Morón-Oset
  7. Oliver Hendrich
  8. Miranda Dyson
  9. Mirjam Lisette Adams
  10. Alexander Hull
  11. Marie-Therese Salcher-Konrad
  12. Amy Monaghan
  13. Magda Bictash
  14. Idoia Glaria
  15. Adrian M Isaacs  Is a corresponding author
  16. Linda Partridge  Is a corresponding author
  1. University College London, United Kingdom
  2. Max Planck Institute for Biology of Ageing, Germany
  3. University College of London, United Kingdom

Abstract

G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE151826. All data generated or analysed during this study are included in the manuscript.

Article and author information

Author details

  1. Magda Luciana Atilano

    Genetics, Evolution & Environment, Institute of Healthy Ageing, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3819-2023
  2. Sebastian Grönke

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1539-5346
  3. Teresa Niccoli

    Genetics, Evolution & Environment, Institute of Healthy Ageing, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Liam Kempthorne

    UK Dementia Research Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Oliver Hahn

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Javier Morón-Oset

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Oliver Hendrich

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Miranda Dyson

    Genetics, Evolution & Environment, Institute of Healthy Ageing, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Mirjam Lisette Adams

    UK Dementia Research Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Alexander Hull

    Genetics, Evolution & Environment, Institute of Healthy Ageing, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Marie-Therese Salcher-Konrad

    UK Dementia Research Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Amy Monaghan

    Alzheimer's Research UK UCL Drug Discovery Institute, University College of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Magda Bictash

    Alzheimer's Research UK UCL Drug Discovery Institute, University College of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Idoia Glaria

    UK Dementia Research Institute, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4556-489X
  15. Adrian M Isaacs

    UK Dementia Research Institute, University College London, London, United Kingdom
    For correspondence
    a.isaacs@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  16. Linda Partridge

    Max Planck Institute for Biology of Ageing, Cologne, Germany
    For correspondence
    Linda.Partridge@age.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9615-0094

Funding

Alzheimer's Research UK (ARUK-PG2016A-6)

  • Adrian M Isaacs

Wellcome Trust

  • Linda Partridge

Max-Planck-Gesellschaft (Open-access funding)

  • Linda Partridge

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

Reviewing Editor

  1. Mani Ramaswami, Trinity College Dublin, Ireland

Publication history

  1. Received: May 4, 2020
  2. Accepted: March 9, 2021
  3. Accepted Manuscript published: March 19, 2021 (version 1)
  4. Version of Record published: March 29, 2021 (version 2)

Copyright

© 2021, Atilano 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. Magda Luciana Atilano
  2. Sebastian Grönke
  3. Teresa Niccoli
  4. Liam Kempthorne
  5. Oliver Hahn
  6. Javier Morón-Oset
  7. Oliver Hendrich
  8. Miranda Dyson
  9. Mirjam Lisette Adams
  10. Alexander Hull
  11. Marie-Therese Salcher-Konrad
  12. Amy Monaghan
  13. Magda Bictash
  14. Idoia Glaria
  15. Adrian M Isaacs
  16. Linda Partridge
(2021)
Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila
eLife 10:e58565.
https://doi.org/10.7554/eLife.58565
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