Discovery Links Protein to DNA Repair and Neurodegenerative Diseases
Researchers from Houston Methodist have found that a protein associated with neurodegenerative diseases like dementia and amyotrophic lateral sclerosis (ALS) plays a role in a vital DNA repair process. This system, called DNA mismatch repair, is responsible for correcting errors that occur when cells replicate genetic material. The team’s findings imply that this protein might impact both brain disorders and cancer, which could change how experts view these significant health issues.
The study, featured in Nucleic Acids Research, reveals that the protein ‘TDP43’ is key in regulating genes that fix DNA errors. When TDP43 levels become too low or too high, these repair genes can become overly active, potentially harming neurons and destabilizing the genome, which might elevate the risk of cancer.
TDP43’s Essential Role in DNA Mismatch Repair
“DNA repair is a fundamental biological process,” explained lead investigator Muralidhar L. Hegde, Ph.D., who is a professor of neurosurgery at the Houston Methodist Research Institute’s Center for Neuroregeneration. “Our findings indicate that TDP43 is not merely another RNA-binding protein involved in splicing; it’s a crucial regulator of the mismatch repair machinery. This has significant implications for conditions like ALS and frontotemporal dementia (FTD), where this protein is malfunctioning.”
The researchers also found connections between the protein and cancer. Their examination of extensive cancer databases revealed that higher levels of TDP43 were linked to an increased number of mutations within tumors.
Protein’s Link to Neurodegeneration and Cancer
“This suggests that the role of this protein extends beyond just ALS or FTD,” Hegde noted. “In cancers, TDP43 seems to be upregulated, which correlates with a higher mutation load. This places it at the crossroads of two of today’s most critical disease categories: neurodegeneration and cancer.”
The team believes that these discoveries could lead to new treatment strategies. In laboratory models, decreasing the excessive DNA repair activity caused by abnormal TDP43 helped mitigate cellular damage. Hegde remarked that managing DNA mismatch repair might provide a new therapeutic approach.
Other contributors to the research 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 study received primary support from the National Institute of Neurological Disorders and Stroke (NINDS), along with the National Institute on Aging of the NIH, the Sherman Foundation Parkinson’s Disease Research Challenge Fund, and internal contributions from the Houston Methodist Research Institute.
