Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

Amyotrophic lateral sclerosis (ALS) is a devastating disease that slowly takes away a person's ability to move, walk, speak, and eventually breathe. One of the main troublemakers is a protein called TDP43, which in ALS becomes misshapen and starts acting like an unwelcome conqueror, building toxic "forts" inside cells and pushing its influence from one cell to the next. But we still don't know exactly how it spreads its harmful territory. Recently, scientists found something surprising: some proteins that we thought lived only inside the cells appear on the cell's outer surface, almost like flags/border guards planted at the borders of a kingdom. In our lab, we discovered that TDP43 plants its flag there too, right on the surface of human motor neurons, which are the main targets in ALS. If TDP43 is sitting at the borders, in misbehaved environments, it may act like an evil colonizer sending out signals, crossing into neighboring cells, and expanding its toxic territory. With this on mind, my research explores this idea in three steps: First, we will map if ~ 200 "border guards", can be found on the surface of healthy motor neurons. We want to know who is standing where: on the main cell body, along the neural "roads," or at synapses, where neurons talk to each other. Next, I will look at neurons made from ALS patients and ask: Do their borders look different? Are there more guards/flags, or patterns that might explain why their cells are more vulnerable to invasion? Finally, I will also investigate whether surface-exposed TDP43 behaves like a conqueror, leaving one cell, entering another, and spreading toxicity or "its evil done". I will also look whether ALS-linked genetic changes make this spreading easier or more aggressive. By uncovering what TDP43 is doing on the borders of cells, we may find new ways to block its advancement. Stopping this "border crossing" can help slow/prevent the progression of ALS, offering hope for the development of treatments.