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| Status |
Public on Mar 20, 2021 |
| Title |
Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila |
| Organism |
Drosophila melanogaster |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
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| Overall design |
mRNA profiles from heads of old female control (elavGS/+) and polyGR100 flies
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| Contributor(s) |
Atilano ML, Grönke S, Niccoli T, Kempthorne L, Hahn O, Morón-Oset J, Hendrich O, Dyson M, Adams ML, Hull A, Salcher-Konrad M, Monaghan A, Bictash M, Glaria I, Isaacs AM, Partridge L |
| Citation(s) |
33739284 |
| |
| Submission date |
Jun 04, 2020 |
| Last update date |
Apr 07, 2021 |
| Contact name |
Linda Partridge |
| Organization name |
Max Planck Institute for Biology of Ageing
|
| Department |
Biological Mechanisms of Ageing
|
| Street address |
Joseph-Stelzmann-Straße 9B
|
| City |
Köln |
| ZIP/Postal code |
50931 |
| Country |
Germany |
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| Platforms (1) |
| GPL17275 |
Illumina HiSeq 2500 (Drosophila melanogaster) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA637376 |
| SRA |
SRP266185 |
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