Investigating inhibition of TDP-43 propagation as a therapeutic strategy for ALS

Abnormalities in a protein called TDP-43 are present in approximately 97 per cent of all ALS cases. Typically residing in the nucleus of a cell (a central compartment housing our DNA) TDP-43 is often found in the cytoplasm (the region outside the nucleus) in individuals with ALS. In this cytoplasmic location, it tends to form clumps or aggregates, impairing its normal function. It has been hypothesized that TDP-43 may contribute to disease progression through the spread of its toxic aggregated form from cell to cell within the central nervous system.

Recognizing the potential significance of TDP-43 propagation in ALS pathology, Dr. Parker and his team will use this award to develop animal models for studying the transfer of TDP-43 proteins between motor neurons. In Dr. Parker’s lab, they specialize in using small worms called C. elegans, measuring only a millimeter in length. Due to their short lifespans and a genetic makeup sharing 60 percent similarity with humans, these worms are well-suited for research purposes.

Using the C. elegans model, researchers will have a unique opportunity to observe and manipulate potentialTDP-43 propagation in a living environment, providing insights that have been challenging to obtain in other model systems. Furthermore, the team plans to screen for molecules that can halt the possible spread of TDP-43in this system. Lead candidates will be tested in a human model system, which if successful, the team hopes would eventually progress to clinical studies. Ultimately, the proposed research aims to identify molecules that could block the spread of TDP-43 and potentially pave the way for developing new therapeutics.