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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The RNA exosome plays a critical role in surveilling nuclear mRNA biogenesis and regulating co-translational mRNA decay in the cytoplasm. Unlike canonical translation, repeat-associated non-AUG (RAN) translation of a GGGGCC hexanucleotide repeat expansion (HRE) within an intron of the C9orf72 locus leads to the synthesis of neurotoxic dipeptide-repeat (DPR) proteins, contributing to the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis (C9-ALS\/FTD). However, it remains unclear whether aberrant RAN translation is monitored and regulated co-translationally or how C9orf72 HRE (C9-HRE) mRNA is degraded during this process. Here, we demonstrate that RAN translation triggers the rapid decay of C9-HRE mRNA. During this process, the RNA exosome engages the translating ribosome-C9-HRE mRNA complex to mediate RAN translation-coupled mRNA decay. Moreover, overexpression of EXOSC3, a key subunit of the RNA exosome cap, promotes RAN translation-coupled decay of C9-HRE mRNA and suppresses DPR production. In iPSC-derived neurons, a reduction in EXOSC3 levels blocks C9-HRE mRNA decay in a translation-dependent manner, further confirming its role in RAN translation surveillance. These findings highlight the essential function of the RNA exosome, particularly EXOSC3, in mitigating RAN translation-associated toxicity and preventing pathological DPR production. This work provides insights into potential therapeutic strategies for C9-ALS\/FTD and may have broader implications for other disorders involving RAN translation.<\/jats:p>","DOI":"10.3390\/ijms27156986","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:02:19Z","timestamp":1785830539000},"page":"6986","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RAN Translation-Coupled Decay of the C9orf72 GGGGCC Repeat Transcript by the RNA Exosome Suppresses Dipeptide Repeat Production"],"prefix":"10.3390","volume":"27","author":[{"given":"You","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tian","sequence":"additional","affiliation":[{"name":"Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilei","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunzhao","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Shao","sequence":"additional","affiliation":[{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"},{"name":"Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianlin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"},{"name":"Institute of Pediatrics, Children\u2019s Hospital, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1722-023X","authenticated-orcid":false,"given":"Xin","family":"Cao","sequence":"additional","affiliation":[{"name":"Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8177-0298","authenticated-orcid":false,"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/s41580-023-00624-9","article-title":"The molecular basis of translation initiation and its regulation in eukaryotes","volume":"25","author":"Querido","year":"2024","journal-title":"Nat. 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