Houston Methodist Study Identifies TDP43 as a Key Regulator of DNA Mismatch Repair Pathway in ALS, FTD

A Houston Methodist research team has uncovered a novel role for the RNA/DNA-binding protein TDP43, showing that it directly regulates DNA mismatch repair (MMR) genes — a finding that could reshape understanding of both neurodegenerative disease and cancer.

The study demonstrates that loss or overexpression of TDP43 — long implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) — alters the expression of core MMR genes such as MLH1 and MSH6 by affecting pre-mRNA splicing and transcript stability.

"DNA repair is one of the most fundamental processes in biology," said Muralidhar L. Hegde, Ph.D., the study's primary investigator and a director 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 FTD where TDP43 goes awry."

The study was published in Nucleic Acids Research in September.

Connecting DNA repair to neurodegeneration

TDP43 proteinopathy — a condition characterized by nuclear depletion and toxic cytoplasmic aggregation of proteins in the brain — is a hallmark in more than 95% of ALS and FTD cases. Dr. Hegde's group had previously shown that TDP43 is required for double-strand break repair. The new work extends this to DNA mismatch repair, a pathway essential for maintaining replication fidelity and genomic stability.

"In neurons, mismatch repair is supposed to be limited because these are non-dividing cells," Dr. Hegde explained. "But in ALS and FTD patient brain tissue, we saw the opposite — a moderate overexpression of MMR proteins. That overactivation can actually be toxic, introducing DNA breaks and instability."

Mouse models of ALS confirmed the pattern: early-stage TDP43 pathology induced compensatory overexpression of mismatch repair proteins, which in turn drove DNA damage markers.

"It was surprising to us," Dr. Hegde said. "We expected down regulation, but instead found that neurons overcompensate. This hyperactivation may be a key driver of genome instability in neurodegeneration."

A bridge between neurodegeneration and cancer

In collaboration with MD Anderson Cancer Center's John Tainer, Ph.D., an internationally recognized expert in structural biology of DNA repair and his colleague Albino Bacolla, Ph.D., an expert in bioinformatics, the study explored the Cancer Genome Atlas (TCGA) database, revealing significant correlations between TDP43 levels, mismatch repair gene expression and mutational burden across multiple cancer types.

"This tells us the biology is broader than just ALS or FTD," Dr. Hegde said. "In cancers, TDP43 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."

Potential for therapeutic targeting

By knocking down mismatch repair proteins in cell models, the Houston Methodist team demonstrated partial rescue of DNA damage induced by TDP43 pathology. The results suggest that mismatch repair hyperactivation, not just TDP43 aggregation, could be targeted for intervention.

"Controlling DNA mismatch repair may offer a therapeutic strategy," Dr. Hegde noted. "If we can fine-tune this pathway in non-dividing cells, we may be able to slow genome instability and disease progression in ALS and FTD."

Future directions include testing whether mismatch repair overactivation triggers repeat expansions in disorders such as Huntington's disease, and whether TDP43/MMR dysregulation could be exploited as a biomarker or therapeutic entry point in oncology.

Collaborative effort across leading institutions

This research represents a major multi-institutional collaboration led by Dr. Hegde, who brought together leading experts across neuroscience, DNA repair and structural biology.

The findings highlight Houston Methodist's growing role as a leader in translational neuroscience and genome stability research.

"This work illustrates how interconnected neurodegeneration and cancer biology can be — and offers a strong jumping off point for looking more closely at the mechanisms of DNA repair in the context of human disease," Dr. Hegde concluded.

Dr. Gavin Britz, chair of Neurosurgery at Houston Methodist, provided clinical direction linking the mechanistic findings to translational relevance. Dr. Zuoshang Xu (UMass Chan Medical School) contributed a second ALS rodent model validating TDP43–mediated mismatch repair dysregulation. Dr. Ralph Garruto (Binghamton University, SUNY) provided ALS patient tissue samples confirming these alterations in human disease. Emeritus professor Dr. Sankar Mitra (Houston Methodist) offered mechanistic insights into transcription-coupled DNA repair that informed the study's conceptual framework. Drs. Albino Bacolla and John A. Tainer (MD Anderson Cancer Center) analyzed TCGA datasets to establish TDP-43–MMR correlations in cancer, revealing the broader implications of the work across disease contexts. Dr. Guo-Min Li, a mismatch repair pioneer at UT Southwestern, provided crucial conceptual insights on MMR regulation. Dr. Vincent Provacek, who worked in Dr. Hegde's lab as a pre-doctoral trainee and is now a neurosurgeon in Austin, was the paper's first author.