An abnormally long six-letter repeat in the genetic code is the most common cause of two neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Xin Jiang, PhD

These expanded repeats in the C9ORF72 gene may cause disease through two intertwined toxic mechanisms: accumulation of repeat RNAs into foci and production of dipeptide repeat (DPR) proteins, which are abnormal proteins generated from the repeat RNAs.

Unravelling the respective contribution of these two toxic products to disease pathogenesis has been a longstanding challenge.  Using mouse models and patient-derived neurons, a research team led by Xin Jiang, PhD, and Clotilde Lagier-Tourenne, MD, PhD, in collaboration with Franck Martin, PhD (University of Strasbourg, France), provides compelling evidence that DPRs are the primary driver of disease progression rather than repeat RNA. This sets DPRs up as an important target for therapeutic intervention.

To determine the source of toxicity, the researchers used two preclinical models: mice given the human C9ORF72 repeat sequence and neurons derived from ALS/FTD patients. In both models, precise editing of a single nucleotide upstream of the repeat attenuated the production of DPRs without altering the formation of RNA foci. They found that removing the toxic DPR proteins, while

Clotilde Lagier Tourenne, MD, PhD

leaving repeat RNA, mitigated symptoms in mice. In cultured neurons, lowering DPR amounts promoted cell survival and rescued both neuroinflammation and gene expression changes. The authors conclude that repeat RNA alone is not sufficient to cause disease-like pathology in mice and cultured neurons; major disease features only appeared when DPR proteins were produced.

Published in Science on February 5, 2026 | Read the paper

Summary reviewed by: Xin Jiang, PhD, lead author, and Clotilde Lagier-Tourenne, MD, PhD, senior author