Study identifies protein interactions as potential pathway to cure ALS

In Canada, thanks to philanthropy, a team of researchers from the University of Western Ontario led by Dr. Michael Strong has discovered a potential path to a cure for amyotrophic lateral sclerosis (ALS).

The study, which illustrates how protein interactions can preserve or prevent the death of nerve cells that are the hallmark of ALS, is the culmination of decades of research supported by the Temerty Foundation.

"As a physician, it's very important to me to be able to say to a patient or their family, 'We're trying to stop this disease,'" said Strong, a clinician-scientist who has dedicated his career to finding a cure for ALS. “It took 30 years of work to get here; 30 years of caring for families and patients and their loved ones when all we had was hope. This gives us reason to believe that we have discovered a path to a cure.”

ALS, also known as Lou Gehrig's disease, is a debilitating neurodegenerative disease that progressively impairs the functioning of the nerve cells responsible for muscle control, leading to muscle wasting, paralysis and ultimately death. The average life expectancy of a patient with ALS after diagnosis is only two to five years.

In a study published in the journal Brain, Strong's team found that targeting an interaction between two proteins present in nerve cells affected by ALS can stop or reverse the progression of the disease. The team also identified a mechanism that makes this possible.

"Importantly, this interaction could be key to developing treatments not only for ALS, but also for other related neurological conditions such as frontotemporal dementia," said Strong, who holds the Arthur Professorship in ALS Research J. Hudson at the Schulich School of Medicine and Dentistry at Western University. “This is a game changer.”

In almost all ALS patients, a protein called TDP-43 is responsible for the formation of abnormal clots inside cells, causing them to die. In recent years, Strong's team discovered a second protein, called RGNEF, which functions opposite to TDP-43.

The team's latest breakthrough identified a specific fragment of this RGNEF protein, called NF242, that may mitigate the toxic effects of the protein that causes ALS. Researchers have found that when these two proteins interact with each other, the toxicity of the protein that causes ALS is eliminated, significantly reducing damage to nerve cells and preventing their death.

Modeling of TDP-43-NF242 interaction. Source: Brain (2024). DOI: 10.1093/brain/awae078

In experiments on fruit flies, this approach significantly increased lifespan, improved motor function and protected nerve cells from degeneration. Similarly, in mouse models, the approach resulted in increased lifespan and mobility, as well as decreased markers of neuroinflammation.

The path to launching the team was paved by the Temerty family's long-term investment in ALS research at Western University - support that Strong calls "truly transformative."

Strong and his team now have a goal of getting their potential treatment into human clinical trials within five years, thanks to a new donation from the Temerty Foundation.

The fund, founded by James Temerty, founder of Northland Power Inc., and Louise Arcand Temerty, will invest $10 million over five years to support the next steps in bringing this treatment to ALS patients.

Dr. Michael Strong, who holds the Arthur J. Hudson Chair in ALS Research at Western University's Schulich School of Medicine and Dentistry, has discovered a protein that may lead to a cure for ALS. Author: Allan Lewis / Schulich School of Medicine and Dentistry.

“Finding an effective treatment for ALS will mean so much to people living with this terrible disease and to their loved ones,” said James Temerty. “Western University is pushing the boundaries of knowledge about ALS, and we are excited to contribute to the next phase of this breakthrough research.”

The Temerty Foundation's new donation brings the family's total investment in neurodegenerative disease research at Western University to $18 million.

“Dr. Strong's tireless dedication to his work is matched by the Temerty family's deep desire to make a difference for the thousands of people around the world who have been diagnosed with this devastating disease,” said Western University President Alan Shepard. “The Temerty Foundation's investment and vision has accelerated progress in finding an effective treatment for ALS. We are grateful to the Temerty family for their commitment to life-changing research."

“This is a turning point in ALS research that can truly change the lives of patients,” said Dr. John Yu, dean of the Schulich School of Medicine and Dentistry.

“Thanks to Dr. Strong's leadership, our continued investment in the best tools and technologies, and the support of the Temerty Foundation, we are pleased to announce a new era of hope for patients with ALS.”

The results of the work are described in detail in an article published in Brain magazine.