{"doi":"10.7554/elife.58565","title":"Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila","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 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.","journal":"eLife","year":2021,"id":168470,"datarank":0.775605761806128,"base_score":3.4339872044851463,"endowment":3.4339872044851463,"self_citation_contribution":0.515098080672772,"citation_network_contribution":0.260507681133356,"self_endowment_contribution":0.515098080672772,"citer_contribution":0.260507681133356,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":18,"citers_with_citation_signal":16,"citers_with_endowment":16,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9393,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE151826"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":262160,"name":"Sebastian Grönke","orcid":"0000-0002-1539-5346","position":1,"is_corresponding":false},{"id":697847,"name":"Teresa Niccoli","orcid":"0000-0001-9337-0411","position":2,"is_corresponding":false},{"id":697848,"name":"Liam Kempthorne","orcid":"0000-0002-9790-8968","position":3,"is_corresponding":false},{"id":646657,"name":"Oliver Hãhn","orcid":"0000-0001-9015-4545","position":4,"is_corresponding":false},{"id":697849,"name":"Javier Morón-Oset","orcid":"0000-0002-2230-0288","position":5,"is_corresponding":false},{"id":697850,"name":"Oliver Hendrich","orcid":"0000-0003-1185-520X","position":6,"is_corresponding":false},{"id":471542,"name":"Miranda C. Dyson","orcid":"0000-0003-0845-662X","position":7,"is_corresponding":false},{"id":698612,"name":"Mirjam L. Adams","orcid":null,"position":8,"is_corresponding":false},{"id":697851,"name":"Alexander Hull","orcid":"0000-0002-9700-4926","position":9,"is_corresponding":false},{"id":698613,"name":"Marie-Therese Salcher-Konrad","orcid":null,"position":10,"is_corresponding":false},{"id":697852,"name":"Amy E. Monaghan","orcid":"0000-0003-0302-6989","position":11,"is_corresponding":false},{"id":697853,"name":"Magda Bictash","orcid":"0000-0002-7909-8076","position":12,"is_corresponding":false},{"id":697854,"name":"Idoia Glaria","orcid":"0000-0003-4556-489X","position":13,"is_corresponding":false},{"id":697855,"name":"Adrian M. Isaacs","orcid":"0000-0002-6820-5534","position":14,"is_corresponding":false},{"id":262161,"name":"Linda Partridge","orcid":"0000-0001-9615-0094","position":15,"is_corresponding":false},{"id":697846,"name":"Magda L. Atilano","orcid":"0000-0002-3819-2023","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-18T23:46:06.853307Z","pmid":"33739284","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}