| Autor: |
Magda L Atilano, Sebastian Grönke, Teresa Niccoli, Liam Kempthorne, Oliver Hahn, Javier Morón-Oset, Oliver Hendrich, Miranda Dyson, Mirjam Lisette Adams, Alexander Hull, Marie-Therese Salcher-Konrad, Amy Monaghan, Magda Bictash, Idoia Glaria, Adrian M Isaacs, Linda Partridge |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 10 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.58565 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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