Overhearing one conversation was all it took to spark a new idea that became a funded ALS research project.
Terry Suk, a PhD student working in the lab of Dr. Maxime Rousseaux at the University of Ottawa, heard Dr. Rousseaux and another student discuss a list of proteins in the brain that are modified by “SUMOs” (small ubiquitin-like modifiers). SUMOs are small proteins that attach to other proteins and control how they behave, react to stress, and where they are located in cells.
Suk knew that in almost all cases of ALS, TDP-43 protein tends to leave the nucleus of motor neurons and form clumps in the cytoplasm. He had also read a few papers by scientists who had observed correlations between SUMOs and TDP-43. Suk thought that if SUMOs were found on TDP-43, it stands to reason that they might be doing something important.
He asked his colleagues if TDP-43 protein had popped up on their list — and it had! That led Suk to develop a full-fledged research project, together with Dr. Rousseaux, to investigate the effects of SUMOs on TDP-43. With a $75,000 Trainee Award from the ALS Canada Research Program, in partnership with Brain Canada, Suk is receiving multi-year salary support to explore exactly where SUMOs attach to TDP-43 and their potential role in ALS.
“Better understandings of the biology of TDP-43 will advance ALS research,” said Suk. “If SUMOs do play a role in how TDP-43 behaves, that insight will open a door to a whole new avenue of exploration for the development of new treatment targets in the future.”
Exploring a new lead
When SUMOs attach to proteins, that process is called SUMOylation. Suk thinks that SUMOylation may be necessary for the normal function of TDP-43, and if that process doesn’t occur, TDP-43 behaves abnormally. In ALS, TDP-43 sometimes becomes chopped up into smaller pieces. Suk wonders if that results in TDP-43 losing the spot where SUMOylation would normally occur, contributing to ALS disease processes.
To explore these theories, Suk will perform a number of experiments. First, he will identify the exact region where SUMOs tag TDP-43. He already has a good idea where one location might be from his previous work with advanced lab methods. He will also engineer a form of TDP-43 that SUMO can’t recognize to mimic the loss of SUMOylation and see what happens.
Next, he will explore how SUMOylation and TDP-43 interact using fruit fly models. For this part of his project, he will collaborate with Dr. Jeehye Park at SickKids Hospital in Toronto, who is an expert in the field of fruit fly genetics and a recipient of a Project Grant in 2019 from the ALS Canada Research Program. Together they will see if the loss of SUMOylation in fruit flies enhances the toxicity of TDP-43.
Finally, Suk will look for evidence of TDP-43 SUMOylation in human ALS using spinal cord tissue provided in collaboration with Dr. John Woulfe, an expert neuropathologist at the Ottawa Hospital Research Institute.
“It’s exciting to be working on an entirely new area of exploration in ALS research,” said Suk.
Committed to finding answers
Suk was one of the first members of the Rousseaux lab, joining in 2018 as a summer student and starting his PhD in the fall of 2019. According to Dr. Rousseaux, he has been a driving force in establishing ALS research in the lab.
During his undergraduate science degree, Suk became interested in genetics. The more he has learned about ALS, the more he has been drawn in by its complexity, fueling his motivation to study the smallest biological mechanisms.
“A lot of my passion for this work grew from my core interest in how tiny pieces of the puzzle can have massive effects,” Suk said. “By participating in community events like the Walk to End ALS, I’m motivated by meeting people with ALS. This is more than a quest for knowledge; it’s a quest for knowledge and answers that can help people.”