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Researchers at Houston Methodist have discovered that a protein linked to neurodegenerative diseases such as dementia and amyotrophic lateral sclerosis (ALS) also regulates a vital DNA repair process. This repair mechanism, called DNA mismatch repair, corrects errors that occur when cells replicate genetic material. The finding suggests that this protein may influence both brain disorders and cancer, potentially changing how scientists understand these major health challenges.
The study, published in Nucleic Acids Research, reveals that the protein TDP43 controls genes responsible for correcting DNA errors. When TDP43 levels are either too low or too high, these repair genes become excessively active. Rather than protecting cells, this overactivity can damage neurons and destabilize the genome, which may increase cancer risk.
TDP43 Plays a Critical Role in DNA Mismatch Repair
"DNA repair is one of the most fundamental biological processes," said lead investigator Muralidhar L. Hegde, Ph.D., professor of neurosurgery at the Houston Methodist Research Institute's Center for Neuroregeneration. "Our findings show that TDP43 is not merely an RNA-binding protein involved in splicing but a crucial regulator of the mismatch repair machinery. This has significant implications for diseases like ALS and frontotemporal dementia (FTD), where this protein malfunctions."
The researchers also found evidence linking TDP43 to cancer. By analyzing extensive cancer databases, they observed that higher TDP43 levels correlated with increased mutation counts in tumors.
Protein Links Neurodegeneration and Cancer
"This indicates that the biological role of TDP43 extends beyond ALS and FTD," Hegde explained. "In cancer, this protein appears upregulated and associated with a higher mutation burden. This places it at the crossroads of two critical disease categories: neurodegeneration and cancer."
The team suggests these insights could lead to new treatment strategies. In laboratory models, reducing the excessive DNA repair activity caused by abnormal TDP43 partially reversed cellular damage. Hegde noted that modulating DNA mismatch repair might offer a therapeutic approach.
Other collaborators on the study include Vincent Provasek, Suganya Rangaswamy, Manohar Kodavati, Joy Mitra, Vikas Malojirao, Velmarini Vasquez, Gavin Britz, and Sankar Mitra from Houston Methodist; Albino Bacolla and John Tainer from MD Anderson Cancer Center; Issa Yusuf and Zuoshang Xu from the University of Massachusetts; Guo-Min Li from UT Southwestern Medical Center; and Ralph Garruto from Binghamton University.
The research was primarily funded 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 support from the Houston Methodist Research Institute.
