Our understanding of cell biology has been revolutionized in the past decade, leading to new insights on how motor neurons degenerate at the cellular level. Early-career researchers Ji-Young Youn at The Hospital for Sick Children (SickKids) and Hyun Kate Lee, at University of Toronto, Biochemistry Department, are at the forefront of understanding these fundamental biological processes.

With the help of an ALS Canada-Brain Canada Discovery Grant, the co-investigators are using cutting-edge technology to identify undiscovered ways proteins interact within a motor neuron. This deeper understanding could lay the groundwork for the discovery of new targets for therapeutic interventions for ALS patients.

The fuss about FUS

One of the most prominently studied causes of ALS is a gene called FUS. FUS usually lives in the nucleus of a cell, but in ALS patients with FUS mutations, the protein ends up in the cytoplasm and is found as rigid, insoluble aggregates.

In her postgraduate research, Dr. Lee discovered that FUS proteins in a test tube can easily come together to form liquid-like compartments, like how oil separates from water through a process called ‘phase separation’. She also uncovered that FUS morphs through different states, from liquid to gel, then solids structures that resemble aggregates – that we see in FUS-ALS patients.

While researchers know this strange process of aggregation is happening in the cells of many ALS patients, they still don’t fully understand why or how this mislocalization, phase transition, and aggregation takes place – or what makes it toxic to someone’s motor neurons.

Her discovery provided a new outlook on understanding disease of protein aggregation. However, when she came to University of Toronto as a new principal investigator, she knew there were still many missing pieces to the biological puzzle.

Fortunately, Dr. Youn was arriving to this problem from a different angle. Her postdoctoral work focused on using BioID to understand the identity of stress granules, a cytoplasmic compartment (or biomolecular condensate) made up of proteins that are very similar to FUS. Mutations in FUS or different cellular stress was shown to cause this protein to localize to stress granules. Drs. Youn and Lee became interested in this inseparable link and wanted to identify proteins that bring FUS to stress granules in motor neurons and whether they contribute to changes in FUS states. BioID is a powerful technique that allows researchers to “watch” what proteins were in close contact with each other in living cells, offering crucial insights into fundamental biological processes.

It was a match made in ALS-research heaven.

Powered by the Discovery Grant, Dr. Lee and Dr. Youn are now combining their expertise to shed light on what’s really going on inside a cell – and how it impacts neuronal degeneration in ALS.

“We want to understand the biology,” said Dr. Youn, “But we also want to address it. We want to really understand what’s going on with the disease: What is accelerating or protecting the degeneration of motor neurons? By revealing novel interactors, we can find potential regulators that we can modify. That provides a huge potential for new therapeutics.”

Dr. David Taylor, Vice President of Research for the ALS Society of Canada, sees huge potential for this particular collaboration.

Investing in early-stage researchers

The ALS Canada-Brain Canada Discovery Grant is one of the first grants for both researchers. It has injected a sense of energy into their innovative research.

“The grant allowed our joint effort to come together and make this project move forward,” said Dr. Youn. “This is just the starting point. We’re just coming in new, and this grant is fueling the energy and our enthusiasm to push more interdisciplinary, collaborative work together.”

According to Dr. Catherine Ferland, Chief Research and Programs Officer at Brain Canada, investing in young researchers is a priority for both ALS Canada and Brain Canada.

“Early-career researchers are the active doers of tomorrow. Providing them with the resources to gain knowledge and develop expertise early in their careers is critical to solving both current and future problems,” she said. “The contribution that these researchers bring to the scientific community must be acknowledged and encouraged through funding programs.”

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 benefits of partnerships like the one between Brain Canada and the ALS Society of Canada goes far beyond much-needed financial investments in ALS research,” says Dr. Ferland. “Any time we can further our understanding of a rare and debilitating brain disease like ALS, we open the door to a more hopeful future.”

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 Foundation, 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