CFR Researchers Identify Key TDP-43 Partners

Dr. Chantelle Sephton in the laboratory of CFR Investigator Dr. Gang Yu at the University of Texas Southwestern Medical Center at Dallas is first author on their recently reported study of TDP-43 (TAR DNA-binding protein 43) binding partners. Their work, published in the Journal of Biological Chemistry where it was awarded “Paper of the Week,” describes the RNAs and proteins that TDP-43 interacts with in neuronal cells.

Approximately 50% of frontotemporal dementia patients exhibit mislocalization of TDP-43. Researchers have long suspected that mislocalized TDP-43 might sequester binding partners and prevent them from doing their jobs, thus contributing to disease pathogenesis. With over 4,000 interactors reported in this study, it’s clear TDP-43 is involved in a multitude of cellular process. The next step, Dr. Sephton commented, “is to gain a more mechanistic understanding of how altered TDP-43 interactions may lead to disease progression.”

Abnormal TDP-43 localization is also seen in ALS patients and may contribute to other neurodegenerative diseases. Dr. Sephton noted, “One striking finding was that TDP-43 binds to many RNAs that encode for proteins implicated in neurodegenerative diseases such as Alzheimer’s and Parkinsons’. TDP-43 aggregates are also seen in these diseases, therefore this commonality may implicate TDP-43 dysfunction as leading to downstream pathogenesis in those diseases too.”

More research into TDP-43 function from any disease perspective is likely to provide insight into TDP-43’s role in frontotemporal dementia too. Dr. Sephton and team members intend to test some of the exciting hypotheses generated by this foundational work in animal models in the near future.