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Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, but its role in disease pathogenesis is unknown. Here, we show alterations in glucose metabolic pathways and ATP levels in the brains of asymptomatic C9-BAC mice. We find 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 show that one of the arginine-rich DPRs (PR) could directly contribute to glucose metabolism and metabolic stress by inhibiting glucose uptake in neurons. Our findings provide a potential mechanistic link between energy imbalances and C9-ALS\/FTD pathogenesis and suggest a feedforward loop model with potential opportunities for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1038\/s44319-024-00140-7","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T13:01:59Z","timestamp":1714395719000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS\/FTD phenotypes"],"prefix":"10.1038","volume":"25","author":[{"given":"Andrew T","family":"Nelson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-303X","authenticated-orcid":false,"given":"Maria Elena","family":"Cicardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashirekha S","family":"Markandaiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John YS","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7028-0448","authenticated-orcid":false,"given":"Nancy J","family":"Philp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Welebob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5566-3707","authenticated-orcid":false,"given":"Aaron R","family":"Haeusler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piera","family":"Pasinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3893-1348","authenticated-orcid":false,"given":"Giovanni","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0020-6933","authenticated-orcid":false,"given":"Hibiki","family":"Kawamata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6338-6404","authenticated-orcid":false,"given":"Davide","family":"Trotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"140_CR1","doi-asserted-by":"publisher","first-page":"3771","DOI":"10.1093\/brain\/awz302","volume":"142","author":"SP Allen","year":"2019","unstructured":"Allen SP, Hall B, Woof R, Francis L, Gatto N, Shaw AC, Myszczynska M, Hemingway J, Coldicott I, Willcock A et al (2019) C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis. 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