Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in <i>Drosophila</i>.

ABSTRACT: 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 insuli

SUBMITTER: Atilano ML 

PROVIDER: S-EPMC8007214 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature