Project 463179

Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) affects voluntary muscle movements, which deteriorate as motor nerve cells die. This gets worse with time, and 80% of patients die within 5 years of diagnosis, including ~1,000 Canadians each year. Unfortunately, there are no effective treatments because we don't fully understand the molecular details of how ALS effects these neurons. What we do know is that ALS-affected neurons contain aberrant protein plaques called inclusion bodies, which in 97% of cases contain a protein called TAR DNA binding protein (TDP-43). How TDP-43 forms these plaques in ALS is unknown and figuring this out will identify new molecular targets for ALS treatments. The formation of TDP-43 plaques is regulated in part by where it resides in the cell, and we are interested in understanding how TDP-43 localization is controlled in healthy cells and how these controls are altered in ALS. We hypothesize that proteins in various subcellular compartments promote a healthy balance of TDP-43 localization, particularly those in biomolecular condensates. These are formed by a process similar to how oil separates from water and carry out specialized functions. Two of these, stress granules and paraspeckles, are rich in TDP-43 and are dysregulated in ALS. We hypothesize that components in these condensates promote a proper balance between TDP-43's localizations and functions. We will use an innovative discovery technology to systematically identify which proteins determine where TDP-43 goes and how they control its functions in human motor neurons. We predict that TDP-43's interacting proteins help retain it in its proper locations. In ALS, these interactions are modified, leading to aberrant TDP-43 localization and function and the formation of neuronal plaques. The proteins responsible for this regulation will be promising targets for future ALS treatments.