Toxic Protein Buildup, Not RNA, Drives ALS and Frontotemporal Dementia, Latest Research Shows
Groundbreaking research led by Xin Jiang, PhD, and Clotilde Lagier-Tourenne, MD, PhD, has pinpointed the primary driver of nerve damage in C9ORF72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD): toxic proteins, not the RNA repeats previously thought to be the main culprit. The study, published in the journal Science, offers a crucial roadmap for developing targeted therapies for these devastating neurodegenerative diseases.
The C9ORF72 Gene and Neurodegeneration
The most common genetic cause of both FTD and ALS is an expansion of a hexanucleotide repeat in the C9ORF72 gene . This expansion leads to the production of both abnormal RNA structures and dipeptide repeat (DPR) proteins. For years, scientists debated which of these abnormal products was primarily responsible for the neurodegeneration characteristic of these diseases.
Disentangling RNA and Protein Toxicity
To resolve this debate, Dr. Jiang and her team employed CRISPR gene-editing technology. They made a precise alteration to the genetic code that effectively disabled the production of DPRs while leaving the RNA repeats intact. This allowed them to isolate and analyze the effects of each component in both mouse models and neurons derived from patients with ALS/FTD .
“We selectively blocked the toxic protein while leaving the repeat RNAs, and we analyzed the disease progression in different laboratory models, including mouse and cellular models,” explained Dr. Jiang.
Key Findings: DPRs as the Primary Driver
The results were striking. Blocking DPR production mitigated symptoms in mice, and in cultured neurons, lowering DPR levels promoted cell survival and reversed neuroinflammation and gene expression changes. Importantly, the researchers found that repeat RNA alone was insufficient to cause disease-like pathology.
“C9ORF72 disease is complex because the inherited mutation results in several abnormal products that may damage brain cells,” said Dr. Lagier-Tourenne. “Determining if these abnormal products contribute to disease is crucial for the development of effective therapies because researchers need to know what to target. We made the unexpected observation that repeat RNAs alone did not trigger neurodegeneration. Instead, toxic proteins called DPRs were found to be major contributors to disease, and blocking their synthesis prevented disease progression in mice.”
Implications for Future Therapies
This discovery has significant implications for the development of new treatments for C9ORF72-related ALS and FTD. By identifying DPRs as the primary driver of disease, researchers can now focus on therapies aimed at “turning off” the production of these toxic proteins. Recent research is similarly exploring RNA-targeting CRISPR systems, like CasRx, to reduce both repeat-derived RNAs and DPRs .
“It is a particularly challenging disease, and we are really excited that our study gave an answer to a long-standing question, and hopeful that it will assist designing new therapeutic strategies,” Dr. Jiang stated.
About the Researchers
Xin Jiang, PhD, is a researcher in Clotilde Lagier-Tourenne’s laboratory, focusing on the translation of dipeptide repeats in C9orf72-related ALS/FTD . Clotilde Lagier-Tourenne, MD, PhD, leads the lab and collaborated with Franck Martin, PhD (University of Strasbourg, France) on this research.