TDP-43 is a protein that lives in the nucleus of our cells. But in at least 97 per cent of ALS patients, TDP-43 somehow finds its way out of the nucleus – also called “mislocalization” – and starts to “clump” up in the cell. There are still a number of questions to answer about this process: is it the loss of TDP-43 in the nucleus of motor neurons that leads to symptoms? Or is it the presence of these unusual clumps in the wrong place that causes trouble? Maybe both?

Because it is such a common phenomenon in patients, many current ALS studies are dedicated to finding out the whats and whys of this mislocated protein.

That includes Dr. Maxime Rousseaux, a neuroscientist at the University of Ottawa. He and his team are using an ALS Canada-Brain Canada Discovery Grant to dig deeper into the biology of TDP-43 mislocalization, particularly how a process called SUMOylation might be involved. What they find could lead to a better understanding of one of the most common biological markers of ALS – and new avenues for treatment.

The key question: why cells go from healthy to not healthy

One of Dr. Rousseaux’s primary research focuses is understanding how and why proteins end up in the wrong place in cells involved in neurodegenerative diseases such as Parkinson’s. But this new focus on ALS was inspired by a doctoral student in his lab, Terry Suk, who received a Trainee Award in 2019 supported by ALS Canada and Brain Canada.

“Terry has really been the driving force behind this research, intellectually and experimentally,” said Dr. Rousseaux.

Terry came to the Rousseaux lab in 2018 with a nagging question in his mind: how do cells go from being healthy to not healthy?

“It’s a bit of an obsession at this point,” Terry said.

Under Dr. Rousseaux’s guidance, Terry had been studying SUMOylation, a standard biological process that regulates different functions in a cell. Very few researchers, however, have looked at how SUMOylation might work in relation to TDP-43. Terry wondered: is there a link between TDP-43 mislocalization and SUMOylation that hasn’t been seriously considered yet?

This question led to their Discovery Grant, which is powering a number of experiments to explore the connection between SUMOylation and TDP-43. In one experiment, they are blocking TDP-43 SUMOylation in mice to see if ALS-like symptoms develop. Another will explore ways to monitor SUMOylation in human samples (as opposed to animal models), which could lead to a new biomarker for ALS.

“Dr. Rousseaux and his team are trying to better understand the biology to see if it’s relevant in helping researchers find a way to treat the disease,” said Dr. David Taylor, Vice President of Research for the ALS Society of Canada. “Every little bit we can uncover is a step in the right direction for people living with ALS.”

A reconnection at the right time

One of Dr. Rousseaux’s key collaborators on the project is Dr. Martin Duennwald, a cell biologist at Western University – who also happened to be one of Terry’s undergraduate honors thesis advisors. The researchers connected after Dr. Duennwald heard Terry give a presentation on an earlier iteration of the research at an ALS Canada Research Forum.

“He messaged me saying, ‘This is really cool. Can we talk about it?’” Dr. Rousseaux said.

Now they are working together on a high-potential project that could illuminate key biological mechanisms potentially involved in ALS.

“We appreciate when a Discovery Grant can fund this type of cross-institutional collaboration,” said Dr. Catherine Ferland, Chief Research and Programs Officer at Brain Canada. “When resources and talent come together like this, the potential for impact becomes much greater.”

Motivated by an inspiring community

Dr. Rousseaux said he is excited that the Discovery Grant is allowing him to focus a larger portion of his lab time and resources on ALS – something he has found rewarding so far.

“I am extremely inspired by how organized and motivated the ALS community is,” he said, noting that despite being relatively new to ALS research, the community has embraced him wholeheartedly. “I have felt incredibly welcomed to the community, and am so grateful for its willingness to fund us, even at this early stage of research.”

“It just makes me want to work that much harder,” he added.

Funding that makes an impact

Since 2014, ALS Canada’s partnership with Brain Canada has resulted in more than $24 million being invested in leading-edge ALS research that has helped further understanding of the disease. The Discovery Grant Program is designed to fuel innovation that will accelerate our understanding of ALS, identify pathways for future therapies and optimize care to improve quality of life for people and families affected by this devastating disease. In 2022, nine projects awarded through the 2021 Discovery Grant Program will benefit from $1.125 million in funding.

The Discovery Grant Program has been made possible with the financial support of Health Canada, through the Canada Brain Research Fund, an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada, and of the generosity of provincial ALS Societies, ALS Canada donors and community-based efforts, including 40 per cent of net proceeds from the Walk to End ALS.

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Posted in: Research