Washington DC: Scientists at Houston Methodist have uncovered a surprising new role for a protein long associated with devastating brain diseases, finding that it also plays a critical part in controlling how cells repair DNA copying errors — a discovery that could have major implications for both neurodegenerative disease and cancer research.
The study, published in the journal Nucleic Acids Research, centres on a protein called TDP43, which has previously been linked to conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
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The Houston Methodist team found that TDP43 regulates genes responsible for DNA mismatch repair — the biological system that corrects mistakes made when cells copy their genetic material.
The key finding is what happens when TDP43 levels go wrong. Whether the protein drops too low or rises too high, the DNA repair genes it controls become overactive. Rather than protecting cells, this excessive repair activity ends up harming neurons and destabilising the genome — potentially raising the risk of cancer.
Lead investigator Muralidhar L. Hegde, PhD, Professor of Neurosurgery at the Houston Methodist Research Institute's Centre for Neuroregeneration, said the findings reframe how scientists should think about this protein.
"DNA repair is one of the most fundamental processes in biology," Hegde said.
"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 where this protein goes awry," he added.
Beyond neurodegeneration, the researchers also found evidence connecting TDP43 to cancer. By analysing large cancer databases, the team identified that higher levels of TDP43 were associated with greater numbers of mutations in tumours.
"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," Hegde said.
The findings may also point toward new therapeutic strategies. In laboratory models, reducing the excessive DNA repair activity caused by abnormal TDP43 levels helped partially reverse cellular damage.
Hegde said that targeting DNA mismatch repair activity could offer a viable treatment approach — one that could potentially be relevant to both neurodegenerative diseases and certain cancers where TDP43 dysregulation plays a role.