{"doi":"10.1101/2023.06.07.544100","title":"Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes","abstract":"Abstract The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC) n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":408290,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9615,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":812096,"name":"M.E. Cicardi","orcid":"0000-0001-9490-303X","position":1,"is_corresponding":false},{"id":812659,"name":"Shashirekha S. Markandaiah","orcid":null,"position":2,"is_corresponding":false},{"id":75015,"name":"Jing‐Dong J. Han","orcid":"0000-0002-9270-7139","position":3,"is_corresponding":false},{"id":228692,"name":"Nancy J. Philp","orcid":"0000-0001-7028-0448","position":4,"is_corresponding":false},{"id":1187945,"name":"Emily Welebob","orcid":null,"position":5,"is_corresponding":false},{"id":285353,"name":"Aaron R. Haeusler","orcid":"0000-0001-5566-3707","position":6,"is_corresponding":false},{"id":348843,"name":"Piera Pasinelli","orcid":"0000-0002-3385-2707","position":7,"is_corresponding":false},{"id":368949,"name":"Giovanni Manfredi","orcid":"0000-0003-3893-1348","position":8,"is_corresponding":false},{"id":383951,"name":"Hibiki Kawamata","orcid":"0000-0003-0020-6933","position":9,"is_corresponding":false},{"id":348844,"name":"Davide Trotti","orcid":"0000-0001-6338-6404","position":10,"is_corresponding":false},{"id":225249,"name":"Andrew T. Nelson","orcid":"0000-0002-2591-0428","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T01:21:18.414003Z","pmid":"37333144","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":[]}