Researchers at Houston Methodist have identified a new function for the protein TDP43, previously linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The study, published in Nucleic Acids Research, found that TDP43 is involved in regulating DNA mismatch repair—a process crucial for accurate genetic replication and cell health.
The research team discovered that when TDP43 is either absent or overproduced, genes responsible for DNA repair become overactive. This overactivity can damage neurons and destabilize the genome, which may contribute to cancer development.
"DNA repair is one of the most fundamental processes in biology," said lead investigator Muralidhar L. Hegde, Ph.D., professor of neurosurgery at the Houston Methodist Research Institute's Center for Neuroregeneration. "What we found is that TDP43 is not just another RNA-binding protein involved in splicing, but a critical regulator of mismatch repair machinery. That has major implications for diseases like ALS and frontotemporal dementia (FTD) where this protein goes awry."
Further analysis by the researchers showed an association between high levels of TDP43 and increased mutation rates in large cancer datasets. "This tells us that the biology of this protein is broader than just ALS or FTD," Hegde said. "In cancers, this protein appears to be upregulated and linked to increased mutation load. That puts it at the intersection of two of the most important disease categories of our time: neurodegeneration and cancer."
The findings suggest potential new avenues for treatment. By reducing overactive DNA repair mechanisms in laboratory models, researchers were able to partially reverse damage caused by irregularities with TDP43. Hegde noted that controlling DNA mismatch repair could present a therapeutic strategy.
Collaborators on the study included scientists from Houston Methodist; MD Anderson Cancer Center; University of Massachusetts; UT Southwestern Medical Center; and Binghamton University.
The work received primary funding from the National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Aging at NIH, Sherman Foundation Parkinson's Disease Research Challenge Fund, as well as internal support from Houston Methodist Research Institute.
