Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila .

Autor:	Atilano ML; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom.; UK Dementia Research Institute at UCL, London, United Kingdom., Grönke S; Max Planck Institute for Biology of Ageing, Cologne, Germany., Niccoli T; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom.; UK Dementia Research Institute at UCL, London, United Kingdom., Kempthorne L; UK Dementia Research Institute at UCL, London, United Kingdom.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom., Hahn O; Max Planck Institute for Biology of Ageing, Cologne, Germany., Morón-Oset J; Max Planck Institute for Biology of Ageing, Cologne, Germany., Hendrich O; Max Planck Institute for Biology of Ageing, Cologne, Germany., Dyson M; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom.; UK Dementia Research Institute at UCL, London, United Kingdom., Adams ML; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom.; UK Dementia Research Institute at UCL, London, United Kingdom., Hull A; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom., Salcher-Konrad MT; UK Dementia Research Institute at UCL, London, United Kingdom.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom., Monaghan A; Alzheimer's Research United Kingdom UCL Drug Discovery Institute, University College London, London, United Kingdom., Bictash M; Alzheimer's Research United Kingdom UCL Drug Discovery Institute, University College London, London, United Kingdom., Glaria I; UK Dementia Research Institute at UCL, London, United Kingdom.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom., Isaacs AM; UK Dementia Research Institute at UCL, London, United Kingdom.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom., Partridge L; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom.; Max Planck Institute for Biology of Ageing, Cologne, Germany.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Mar 19; Vol. 10. Date of Electronic Publication: 2021 Mar 19.
DOI:	10.7554/eLife.58565
Abstrakt:	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. Competing Interests: MA, SG, TN, LK, OH, JM, OH, MD, MA, AH, MS, AM, MB, IG, AI, LP No competing interests declared (© 2021, Atilano et al.)
Databáze:	MEDLINE
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