{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:50:19Z","timestamp":1789023019220,"version":"build-2803163510"},"reference-count":89,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"819","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,10,8]]},"abstract":"<jats:p>\n            Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell\u2013derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated\n            <jats:italic toggle=\"yes\">ASCC3<\/jats:italic>\n            variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the\n            <jats:italic toggle=\"yes\">Fmr1<\/jats:italic>\n            KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal\n            <jats:italic toggle=\"yes\">Fmr1<\/jats:italic>\n            KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive\u2013like behavior, and social interaction deficits after 1 month in 2-month-old\n            <jats:italic toggle=\"yes\">Fmr1<\/jats:italic>\n            KO mice compared with untreated\n            <jats:italic toggle=\"yes\">Fmr1<\/jats:italic>\n            KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adq3551","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T17:59:46Z","timestamp":1759946386000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-7156","authenticated-orcid":true,"given":"Ji","family":"Geng","sequence":"first","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, 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