Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila.
Magda L AtilanoSebastian GrönkeTeresa NiccoliLiam KempthorneOliver HahnJavier Morón-OsetOliver HendrichMiranda DysonMirjam Lisette AdamsAlexander HullMarie-Therese Salcher-KonradAmy MonaghanMagda BictashIdoia GlariaAdrian M IsaacsLinda PartridgePublished in: eLife (2021)
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.
Keyphrases
- type diabetes
- amyotrophic lateral sclerosis
- glycemic control
- binding protein
- pi k akt
- genome wide
- dna methylation
- insulin resistance
- metabolic syndrome
- single cell
- skeletal muscle
- adipose tissue
- small molecule
- growth hormone
- machine learning
- copy number
- multiple sclerosis
- electronic health record
- artificial intelligence
- cerebral ischemia
- drug induced
- affordable care act