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The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the\n                    <jats:italic>C9orf72<\/jats:italic>\n                    gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2\u03b1 phosphorylation, has been linked to\n                    <jats:italic>C9orf72<\/jats:italic>\n                    expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using\n                    <jats:italic>Drosophila<\/jats:italic>\n                    models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2\u03b1 phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of\n                    <jats:italic>ATX2<\/jats:italic>\n                    , the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    orthologue of\n                    <jats:italic>ATXN2<\/jats:italic>\n                    , rescues motor deficits in these models.\n                    <jats:italic>ATXN2<\/jats:italic>\n                    knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight\n                    <jats:italic>ATXN2<\/jats:italic>\n                    and the ISR as promising therapeutic targets in\n                    <jats:italic>C9orf72<\/jats:italic>\n                    -associated FTD\/ALS.\n                  <\/jats:p>","DOI":"10.1186\/s40478-026-02301-2","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T13:28:30Z","timestamp":1777987710000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis"],"prefix":"10.1186","volume":"14","author":[{"given":"Nikki S.","family":"Harper","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne L.","family":"Sharpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Speranza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravinder","family":"Gulia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey X.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott P.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manpreet S.","family":"Atwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Pickering-Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Livesey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig L.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Prokop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert R.","family":"La Spada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J. 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