Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes

• 成果类型: Article
• 署名作者: Jiang, Xin; Schaeffer, Laure; Patni, Divya; Russo, Tommaso; Lee, Chao-Zong; Aguilar, Corey; Marques, Christine; Jansen-West, Karen; Hruska-Plochan, Marian; Ray-Soni, Ananya; Lim, Su Min; Held, Aaron; Yue, Mei; Castellanos Otero, Paula; Aryal, Sandeep; Beaussant, Hortense D. A. M.; Basu, Himanish; Takakuwa, Hiro; Daughrity, Lillian M.; Ramesh, Nandini; Da Costa, Paulo; A. A. Quadros, Ana Rita; Nolan, Matthew; Reyes, Charles Jourdan F.; Wheeler, Hayden; Moran, Laura C.; Griesman, Grant; Wymann, Benjamin; Trombetta, Bianca A.; Lopez-De-Silanes, Emma Sofia; Canori, Michael; Krishnan, Gopinath; Vieira Souza Da Silva, Yasmim; Eriani, Gilbert; Albers, Mark W.; Arnold, Steven E.; Song, Yuyu; Jain, Ankur; Chiu, Isaac M.; Zhang, Yong-Jie; Gao, Fen-Biao; Wainger, Brian J.; Polymenidou, Magdalini; Petrucelli, Leonard; Martin, Franck; Lagier-Tourenne, Clotilde
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Centre National de la Recherche Scientifique (CNRS); Universites de Strasbourg Etablissements Associes; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Strasbourg; CNRS - National Institute for Biology (INSB); Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; Mayo Clinic; University of Zurich; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Whitehead Institute; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Marine Biological Laboratory - Woods Hole
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv2600
• 发表日期: 2026-02-05
• 页码: eadv2600
• 关键词: frontotemporal lobar degeneration; hexanucleotide repeat; tdp-43 pathology; antisense transcripts; C9ORF72 ALS; proteins; FOCI; expansion; neurodegeneration; toxicity

摘要

GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell-derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.