Journal Article

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

Hahn, Oliver, Glaria, Idoia, Partridge, Linda, Hendrich, Oliver, Niccoli, Teresa, Dyson, Miranda, Hull, Alexander, Salcher-Konrad, Marie-Therese, Monaghan, Amy, Isaacs, Adrian M, Morón-Oset, Javier, Kempthorne, Liam, Grönke, Sebastian, Atilano, Magda L, Bictash, Magda, Adams, Mirjam Lisette

2021

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Analysis / Animals / C9orf72 / C9orf72 Protein - genetics / C9orf72 Protein - toxicity / Cells / Dementia disorders / DNA damage / DNA Repeat Expansion / Drosophila / Drosophila melanogaster - physiology / Female / Frontotemporal dementia / Frontotemporal Dementia - genetics / Gene expression / Genes / Genetic aspects / hexanucleotide repeats / Insects / Insulin / Insulin - physiology / insulin signalling / Insulin-like growth factors / Kinases / Mammalian cells / Neurodegeneration / Neuropeptides / Neuroscience / Ontology / Peptides / Phenotypes / Protein synthesis / Proteins / RNA / RNA sequencing / Signal Transduction / Toxicity