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Main Authors:	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
Format:	Artículo científico
Language:	en
Published:	Science (New York, N.Y.) 2026
Subjects:	Animals Humans Mice Amyotrophic Lateral Sclerosis C9orf72 Protein Codon Dipeptides Disease Models, Animal DNA Repeat Expansion DNA-Binding Proteins Frontotemporal Dementia Induced Pluripotent Stem Cells Motor Neurons Mutation Phenotype Protein Biosynthesis ran GTP-Binding Protein RNA HEK293 Cells Male Female Mice, Inbred C57BL
Online Access:	https://pubmed.ncbi.nlm.nih.gov/41643021/
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Table of Contents:

Blocking RAN translation without altering repeat RNAs rescues -related ALS and FTD phenotypes. 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 Animals Humans Mice Amyotrophic Lateral Sclerosis C9orf72 Protein Codon Dipeptides Disease Models, Animal DNA Repeat Expansion DNA-Binding Proteins Frontotemporal Dementia Induced Pluripotent Stem Cells Motor Neurons Mutation Phenotype Protein Biosynthesis ran GTP-Binding Protein RNA HEK293 Cells Male Female Mice, Inbred C57BL GGGGCC (GC) repeat expansion in 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 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.

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