One break at a time: Uncovering the role of TDP-43 in DNA repair

Inside each cell in our bodies, we have a DNA sequence, which is the blueprint needed to build and maintain a human being. Double-strand breaks (DSBs) are tiny cracks in our DNA that can disrupt healthy cells. An early feature of ALS is DSBs found in motor neurons, the specialized cells in the brain that are responsible for controlling voluntary muscles. Another common feature in most ALS cases is a disruption of the normal levels and function of a protein called TDP-43. Previous research has shown that TDP-43 may play a role in maintaining DNA stability, but exactly how TDP-43 instability may affect DNA damage in motor neurons is still being explored.

Dr. Lin’s research aims to uncover the precise role of TDP-43 in DNA repair and replication within cells. Her research follows the theory that TDP-43 may have a role in the replisome, a molecular machine that helps cells copy their DNA. This is especially important under cellular stress, when DNA damage becomes more likely. Using a technology called single-molecule tracking (SMT), Dr. Lin will observe how TDP-43 behaves at these critical DNA sites under stress.

By shedding light on TDP-43’s involvement in DNA repair, researchers will gain greater insights into how ALS starts in the body, which could aid in earlier detection of the disease and open up new avenues for potential therapies.

In 2006, the landmark discovery that 97% of ALS cases had abnormalities in the biology of a protein called TDP-43 shifted fundamental ALS research significantly. Soon after, it was determined that mutations in the gene encoding TDP-43 could also cause ALS. The ALS Canada Research Program has supported more than thirty research projects investigating TDP-43 pathology in ALS, significantly impacting the field’s evolving understanding of this complex disease and leading us closer to effective treatments.