When Marc Shenouda first learned about ALS as an undergraduate science student, he found himself asking many questions: Why is the average life expectancy only two to five years after diagnosis? Why is there is no cure yet? How can we find better treatments, ones that could extend life by more than a few months? Finding answers to these questions motivated his decision to join the lab of Dr. Janice Robertson at the University of Toronto in 2017.

Now, with a $75,000 Trainee Award from the ALS Canada Research Program, in partnership with Brain Canada and La Fondation Vincent Bourque, Shenouda has the funding support needed to explore these key questions along the pathway of discovering new potential therapies for ALS. He will be pursuing a leading-edge project together with Dr. Robertson, Dr. Donald Weaver, and Dr. Avi Chakrabartty at the University of Toronto looking for a novel experimental compound that has the potential to prevent the abnormal protein behaviour that occurs in a majority of people with ALS. “If we are successful, it could be a key turning point in the field of ALS research,” Shenouda says.

Abnormal protein behaviour

Proteins are long chains of amino acids inside cells that must fold into the right shapes to perform their jobs properly. Misfolded proteins cause problems that have been linked to a number of neurodegenerative diseases, including ALS.

For example, the TDP-43 protein is normally found in the nucleus of motor neurons. However, in 97 per cent of people with ALS, it moves out of the nucleus and then misfolds and forms clumps in the cytoplasm. One scientific theory is that these clumps are toxic to motor neurons. Therefore, figuring out how to stop them from forming could be instrumental in understanding how to potentially prevent ALS.

High-tech computer modelling

For the project, Shenouda started the search for a promising experimental drug using a computer program that models how different compounds fit into the unique “pockets” located on the surface of proteins. “Based on the literature, we believe there is a specific area on TDP-43 between amino acid 318 and 340 where misfolding happens,” says Shenouda. “Sticking a compound into a pocket in that area may prevent TDP-43 from forming aggregates.”

The computer modelling program was developed by Dr. Weaver, a medicinal chemist and neurologist at the University of Toronto who has expertise using the same technique to look for compounds that could potentially prevent clumping of proteins associated with Alzheimer’s disease.

Shenouda screened 50,000 compounds and created a shortlist of 500 potential candidates. Next, he collaborated with Dr. Chakrabartty, a medical biophysics expert, to identify the top 20 compounds that could reduce TDP-43 clumping and toxicity in motor neurons that were generated in the lab. “We have discovered five promising compounds so far,” says Shenouda. “Our best hit reduces aggregation by 50 per cent.”

While the outcomes of these early laboratory tests are exciting, Shenouda is containing his enthusiasm until he completes the final phase of the project. As a next step, he will test the most promising compound in TDP-43 ALS mouse models to see if it can change the course of the disease. If so, that compound could be developed further and studied in a clinical trial.

Shenouda won’t finish his PhD for another three years, but he’s well on his way to establishing a career in ALS research. He is also a teaching assistant for a course on molecular biology techniques at the University of Toronto’s Scarborough campus. “I always start my first practical lab using ALS as an example of why it’s so important to understand proteins and genes and their relevance in real life,” Shenouda says. “I sure hope that inspires some of the students to pursue ALS research.”

This research project is one of 6 Trainee Awards funded in 2019 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. The three-year award will contribute to Shenouda’s salary. The Weston Brain Institute is also supporting the project with a $1 million grant.

The ALS Canada Research Program Trainee Awards

ALS Canada Trainee Awards support Canada’s emerging ALS researchers, whether they are doctoral students, postdoctoral researchers, or clinical research fellows. Trainee awards encourage young researchers to choose ALS as their area of focus, helping to ensure that Canada has a strong base of talented ALS researchers today and into the future.

Funding of the trainee followed a rigorous scientific assessment by a panel of ALS experts. The panellists evaluated a larger pool of applications to identify applicants that demonstrate scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

ALS Canada is a registered charity that receives no government funding. Everything we do – from funding research to providing community-based support for people living with ALS – is possible only because of donor generosity and partnerships with provincial ALS Societies who contribute to the ALS Canada Research Program.

Because of you, the ALS Canada Research Program can continue to fuel the scientific discoveries that further our understanding of ALS. Your support makes a difference.

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Posted in: Research