Scientists Discover Dementia-Linked Protein May Also Fuel Cancer Mutations

A protein long associated with ALS and dementia may also control a critical DNA repair pathway.

Houston Methodist scientists have uncovered an unexpected side of a protein best known for its link to brain diseases. The protein, tied to dementia and amyotrophic lateral sclerosis (ALS), appears to help manage DNA mismatch repair, the cell’s built-in proofreading system that catches typos as DNA is copied.

Because this repair process is essential for preserving genetic information and maintaining healthy cells, the discovery could reshape how scientists think about both cancer and neurodegenerative disease.

The study, published in Nucleic Acids Research, reports that the protein ‘TDP43’ influences the activity of genes responsible for correcting DNA replication errors. When levels of this protein drop or rise too high, the repair genes become overly active. This imbalance can harm neurons and disrupt the stability of 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.”

Evidence Linking TDP43 to Cancer

The researchers also identified a connection between TDP43 and cancer. After examining large cancer data sets, they found that tumors with higher amounts of this protein tend to show greater numbers of genetic mutations.

“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.”

Potential Therapeutic Opportunities

Scientists say the discovery may point toward new treatment strategies. In laboratory experiments, lowering excessive DNA repair activity helped reverse some of the cellular damage caused by abnormal TDP43 function.

Hegde said that controlling DNA mismatch repair could eventually become a therapeutic approach for conditions linked to TDP43 dysfunction.

Reference: “RNA/DNA-binding protein TDP43 regulates DNA mismatch repair genes with implications for genome stability” by Vincent E Provasek, Albino Bacolla, Suganya Rangaswamy, Manohar Kodavati, Joy Mitra, Issa O Yusuf, Vikas H Malojirao, Velmarini Vasquez, Gavin W Britz, Guo-Min Li, Zuoshang Xu, Sankar Mitra, Ralph M Garruto, John A Tainer and Muralidhar L Hegde, 23 September 2025, Nucleic Acids Research.
DOI: 10.1093/nar/gkaf920

The research was primarily supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging of the National Institutes of Health (NIH), the Sherman Foundation Parkinson’s Disease Research Challenge Fund, and internal funding from the Houston Methodist Research Institute.

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