Scientists discover ALS protein that links DNA repair to cancer and dementia

The study, published in Nucleic Acids Research, shows that the protein ‘TDP43’ regulates genes responsible for fixing DNA errors. When levels of this protein drop too low or rise too high, those repair genes become overly active. Instead of protecting cells, the heightened repair activity can harm neurons and destabilize the genome, which may increase the risk of cancer.

TDP43 Plays a Critical Role in DNA Mismatch Repair

“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 researchers also uncovered evidence linking the protein to cancer. By analyzing large cancer databases, the team found that higher amounts of TDP43 were associated with greater numbers of mutations in tumors.

Protein Links Neurodegeneration and Cancer

“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.”

The scientists say the findings may also point toward new treatment approaches. In laboratory models, reducing the excessive DNA repair activity caused by abnormal TDP43 helped partially reverse cellular damage. 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.