Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom
Max Planck Institute for Biology of Ageing, Cologne, Germany
Teresa Niccoli
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom
Liam Kempthorne
UK Dementia Research Institute at UCL, London, United Kingdom; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
Oliver Hahn
Max Planck Institute for Biology of Ageing, Cologne, Germany
Javier Morón-Oset
Max Planck Institute for Biology of Ageing, Cologne, Germany
Oliver Hendrich
Max Planck Institute for Biology of Ageing, Cologne, Germany
Miranda Dyson
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom
Mirjam Lisette Adams
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom
Alexander Hull
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom
Marie-Therese Salcher-Konrad
UK Dementia Research Institute at UCL, London, United Kingdom; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
Amy Monaghan
Alzheimer's Research United Kingdom UCL Drug Discovery Institute, University College London, London, United Kingdom
Magda Bictash
Alzheimer's Research United Kingdom UCL Drug Discovery Institute, University College London, London, United Kingdom
UK Dementia Research Institute at UCL, London, United Kingdom; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
UK Dementia Research Institute at UCL, London, United Kingdom; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, London, United Kingdom; Max Planck Institute for Biology of Ageing, Cologne, Germany
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.
