Researchers at Houston Methodist University have discovered that proteins associated with neurodegenerative diseases such as dementia and amyotrophic lateral sclerosis (ALS) also help control important DNA repair processes. This repair system, known as DNA mismatch repair, corrects mistakes that occur when cells copy genetic material. The discovery suggests that this protein may influence both brain disease and cancer, potentially changing the way scientists think about these major health conditions.
This research Nucleic acid researchshowing that the protein ‘TDP43’ regulates genes involved in DNA error repair. When levels of this protein fall too low or rise too high, repair genes become overactive. Instead of protecting cells, increased repair activity can damage neurons, destabilize the genome, and increase cancer risk.
TDP43 plays an important role in DNA mismatch repair
“DNA repair is one of the most fundamental processes in biology,” said principal investigator Muralidhar L. Hegde, Ph.D., professor of neurosurgery in the Center for Neural Regeneration at Houston Methodist Research Institute. “What we discovered is that TDP43 is not just an RNA-binding protein involved in splicing, but is an important regulator of the mismatch repair machinery. This has major implications for diseases such as ALS and frontotemporal dementia (FTD), where this protein is abnormal.”
Researchers also found evidence linking this protein to cancer. By analyzing a large cancer database, the research team found that the higher the amount of TDP43, the higher the number of mutations within the tumor.
Proteins link neurodegeneration and cancer
“This shows that the biology of this protein is broader than just ALS or FTD,” Hegde said. “In cancer, this protein appears to be upregulated and associated with an increased mutational burden. Thus, this protein lies at the intersection of neurodegeneration and cancer, two of the most important disease categories of our time.”
Scientists say the discovery may suggest new therapeutic approaches. In laboratory models, reducing excessive DNA repair activity caused by aberrant TDP43 helped partially reverse cell damage. Hegde said controlling DNA mismatch repair could provide a therapeutic strategy.
Other collaborators on the study were Houston Methodist’s Vincent Provacek, Suganya Rangaswami, Manohar Kodavati, Joy Mitra, Vikas Marojirao, Belmarini Vasquez, Gavin Blitz, and Sankar Mitra. Albino Bakora and John Tainor of MD Anderson Cancer Center. Issa Yusuf and Zuoshang Xu from the University of Massachusetts. Guo-Min Li of UT Southwestern Medical Center and Ralph Garruto of Binghamton University.
This research was primarily supported by internal funding from 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 Houston Methodist Research Institute.
