Protein Linked to ALS and Dementia Too Plays Role in DNA Repair, Study Finds

A protein long associated with neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and dementia may also be a key regulator of DNA mismatch repair, the cell’s natural proofreading system. This unexpected discovery by Houston Methodist scientists could reshape our understanding of both cancer and neurodegenerative disease.

The study, published in Nucleic Acids Research, reveals that the protein TDP43 influences the activity of genes responsible for correcting errors that occur during DNA replication. Imbalances in TDP43 levels – either too high or too low – can lead to overactive repair genes, potentially harming neurons and destabilizing the genome, which may contribute to cancer development.

TDP43: A Multifaceted Protein

“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.”

Link to Cancer Development

Researchers found a connection between TDP43 and cancer after analyzing large cancer datasets. Tumors with higher amounts of TDP43 tended to have a greater number 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 key disease categories of our time: neurodegeneration and cancer.”

Potential Therapeutic Strategies

The discovery opens doors for potential modern treatment strategies. Laboratory experiments showed that reducing excessive DNA repair activity helped reverse some of the cellular damage caused by abnormal TDP43 function.

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

Research Funding

The research was 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.