A protein linked to neurodegenerative diseases like dementia and amyotrophic lateral sclerosis (ALS) similarly plays a critical role in DNA repair, a discovery that could reshape how scientists approach these and potentially even cancer treatments. The findings, published in Nucleic Acids Research, highlight a surprising connection between brain health and the body’s ability to fix genetic errors.
Researchers at Houston Methodist found that the protein, known as TDP43, regulates genes responsible for correcting errors that occur when cells copy their DNA. This process, called DNA mismatch repair, is essential for maintaining genomic stability. The study revealed that when levels of TDP43 are too high or too low, these repair genes become overactive.
Instead of protecting cells, this increased repair activity can actually damage neurons and destabilize the genome, potentially increasing cancer risk. This dual role suggests TDP43 is a key player in a complex interplay between neurological disease and cancer development.
“DNA repair is one of the most fundamental processes in biology,” explained lead researcher Muralidhar L. Hegde, Ph.D., professor of neurosurgery at the Houston Methodist Institute for Research. “What we found is that TDP43 isn’t just another RNA-binding protein involved in splicing, but a critical regulator of the mismatch repair machinery. This has important implications for diseases like ALS and frontotemporal dementia (FTD) where this protein goes wrong.”
TDP43’s Link to Cancer
Further analysis of large cancer databases revealed a correlation between higher levels of TDP43 and a greater number of mutations in tumors. This finding strengthens the link between the protein’s dysfunction and the development of cancer, suggesting a broader biological role than previously understood.
“This tells us that the biology of this protein is wider than just ALS or FTD,” Hegde said. “In cancer, this protein appears to be elevated and associated with an increased mutational burden. This puts it at the crossroads of two of the most important disease categories of our time: neurodegeneration and cancer.”
The research also suggests potential new therapeutic avenues. In laboratory models, reducing the overactive DNA repair triggered by abnormal TDP43 partially reversed cellular damage. Controlling DNA mismatch repair could offer a novel strategy for treating neurodegenerative diseases and potentially cancer, researchers say.
Other collaborators on the study included Vincent Pravasek, Suganya Rangaswamy, Manohar Kodavathy, Joy Mitra, Vikas Malajirao, Velmarini Vasquez, Gavin Britz and Sankar Mitra of Houston Methodist; Albino Bakola and John Tayner of MD Anderson Cancer Center; Issa Yusuf and Zuoshan Xu, of the University of Massachusetts; Guo-Ming Li, of UT Southwestern Medical Center, and Ralph Garuta, of Binghamton University.
The research was supported in part 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 for Parkinson’s Disease Research, and internal funding from the Houston Methodist Institute for Research.
