Protein tied to ALS and dementia plays a role in regulating DNA mismatch repair

New Houston Methodist research has revealed that a protein associated with neurodegenerative diseases such as dementia and amyotrophic lateral sclerosis (ALS) also plays a role in regulating DNA mismatch repair, a process essential for replicating genetic information and cell health. The finding could change how scientists understand both cancer and neurodegeneration. 

The study, published in Nucleic Acids Research, finds that the protein, 'TDP43' regulates genes that fix DNA mistakes. When this protein is lost or overproduced, these repair genes become overactive, damaging neurons and destabilizing the genome, which could lead to cancer. 

"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." 

The team also found an association between the protein and cancer. Their analysis of large cancer datasets revealed that high levels correlate with increased mutation rates. 

"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 important disease categories of our time: neurodegeneration and cancer." 

Researchers said the discovery opens doors for new treatments. By reducing overactive DNA repair in lab models, they partially reversed damage caused by TDP43 problems. Hegde said that Controlling DNA mismatch repair may offer a therapeutic strategy. 

Other collaborators in the study were 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 University of Massachusetts; Guo-Min Li from UT Southwestern Medical Center and Ralph Garruto from Binghamton University. 

The research was primarily 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.