Xin Jiang, Laure Schaeffer, Divya Patni, Tommaso Russo, Chao-Zong Lee, Corey Aguilar, Christine Marques, Karen Jansen-West, Marián Hruška-Plocháň, Ananya Ray-Soni, Su Min Lim, Aaron Held, Mei Yue, Paula Castellanos Otero, Sandeep Aryal, Hortense D. A. M. Beaussant, Himanish Basu, Hiro Takakuwa, Lillian M. Daughrity, Nandini Ramesh, Paulo J. da Costa, Ana Rita A. A. Quadros, Matthew Nolan, Charles Jourdan Reyes, Hayden J. Wheeler, Laura C. Moran, Grant Griesman, Benjamin Wymann, Bianca A. Trombetta, Emma Sofia Lopez-De-Silanes, Michael Canori, Gopinath Krishnan, Yasmim Vieira Souza Da Silva, Gilbert Eriani, Mark W. Albers, Steven E. Arnold, Yuyu Song, Ankur Jain, I. Chiu, Yong-Jie Zhang, Fen-Biao Gao, Brian J. Wainger, Magdalini Polymenidou, Leonard Petrucelli, Franck Martin, Clotilde Lagier-Tourenne
GGGGCC (G 4 C 2 ) 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.