Blocking RAN translation without altering repeat RNAs rescues <i>C9ORF72</i> -related ALS and FTD phenotypes
GGGGCC (G<sub>4</sub>C<sub>2</sub>) repeat expansion in <i>C9ORF72</i> 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 <i>C9ORF72</i> 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.
Authors
- Divya Patni
- S. R. Arnold (ORCID: https://orcid.org/0000-0002-4881-5685)
- Charles Jourdan Reyes (ORCID: https://orcid.org/0000-0001-5110-7121)
- Sandeep Aryal (ORCID: https://orcid.org/0000-0002-1674-4552)
- François-René Martin
- Matthew Nolan
- Himanish Basu (ORCID: https://orcid.org/0000-0001-8236-1157)
- Lillian M. Daughrity (ORCID: https://orcid.org/0000-0003-4644-7265)
- Marián Hruška-Plocháň (ORCID: https://orcid.org/0000-0002-9253-4362)
- Yuyu Song (ORCID: https://orcid.org/0000-0002-9196-1610)
- Paulo J. da Costa
- Mark W. Albers (ORCID: https://orcid.org/0000-0001-7855-3455)
- Laure Schaeffer
- Aaron Held (ORCID: https://orcid.org/0000-0003-4554-2383)
- I. Chiu
- Tommaso Russo (ORCID: https://orcid.org/0000-0002-3526-5186)
- Christine Marques
- Hiro Takakuwa (ORCID: https://orcid.org/0009-0006-6838-6407)
- Gilbert Eriani (ORCID: https://orcid.org/0000-0002-8518-4675)
- Su Min Lim (ORCID: https://orcid.org/0000-0002-5769-4854)
- Brian J. Wainger (ORCID: https://orcid.org/0000-0002-3664-7231)
- Gopinath Krishnan (ORCID: https://orcid.org/0000-0002-3508-1133)
- Corey Aguilar
- Paula Castellanos Otero
- Michael Canori
- Hayden J. Wheeler
- Mei Yue
- Yong-Jie Zhang
- Nandini Ramesh
- Ananya Ray-Soni
- Emma Sofia Lopez-De-Silanes
- Ana Rita A. A. Quadros
- Yasmim Vieira Souza Da Silva
- Chao-Zong Lee
- Magdalini Polymenidou
- Ankur Jain
- Karen Jansen-West
- Leonard Petrucelli
- Xin Jiang
- Hortense D. A. M. Beaussant
- Clotilde Lagier-Tourenne
- Grant Griesman
- Benjamin Wymann (ORCID: https://orcid.org/0009-0002-3270-9594)
Institutions
- Broad Institute (US)
- Centre National de la Recherche Scientifique (FR)
- Marine Biological Laboratory (US)
- Harvard University (US)
- Vita-Salute San Raffaele University (IT)
- University of Massachusetts Chan Medical School (US)
- University of Zurich (CH)
- Massachusetts General Hospital (US)
- Architecture et Réactivité de l'arN (FR)
- IRCCS Ospedale San Raffaele (IT)
- Mayo Clinic in Florida (US)
- Whitehead Institute for Biomedical Research (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science
- Published
- 2026-02-05
- DOI
- https://doi.org/10.1126/science.adv2600
- Citations
- 1
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 39.15