Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila
- University College London, United Kingdom
- Max Planck Institute for Biology of Ageing, Germany
- 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
Magda Luciana Atilano
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
- Mani Ramaswami, Trinity College Dublin, Ireland
Publication history
- Received: May 4, 2020
- Accepted: March 9, 2021
- Accepted Manuscript published: March 19, 2021 (version 1)
- 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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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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