Nearly 3,000 Canadians live with amyotrophic lateral sclerosis, or ALS. Almost 1,000 people are diagnosed each year and as many will die from the disease. These are the statistics that Christine Vande Velde and Dr. Geneviève Matte, two scientists at the CHUM Research Centre (CRCHUM), want to challenge with basic and clinical research projects. Here is an overview of their work in this ALS Awareness Month.

ALS, also known as Lou Gehrig’s or Charcot disease, is an incurable neurodegenerative disorder characterized by the selective loss of motor neurons. These nerve cells serve as our internal wiring. They allow us to move our body as needed by enabling transmission of signals to the muscles in order to make them contract.

In people suffering from ALS, the motor neurons gradually deteriorate. These patients eventually lose their muscular function to the point of total paralysis, with an average life expectancy of only 3 to 5 years after diagnosis. In concrete terms, a person living with this rare disease loses the ability to walk, speak, eat, swallow, and ultimately, to breathe.

Complex mechanisms

“In our lab, we try to understand what is wrong with the motor neurons from the point of view of their molecular mechanisms. There are two reasons for this: to identify mechanisms that we can target with therapy, and to find biomarkers to track the course of the disease and predict whether it will progress rapidly or slowly,” explains Christine Vande Velde, professor in the Department of Neuroscience at the Université de Montréal and co-Chair of the Scientific and Medical Advisory Council of ALS Canada.

Over the past two years, her team has found that in people with ALS, a protein called TDP-43 is less present in the nuclei of motor neurons. In this case, the level of another protein called G3BP1 decreases and directly influences the formation of stress granules.

In healthy cells, stress granules are protective structures that prevent damage to ribonucleic acid, or RNA, by environmental stresses such as heat or pollution. If the level of the G3BP1 protein, which is essential for neuronal survival, decreases, the motor neurons are more vulnerable to damage.

At this time, Christine Vande Velde is collaborating with CRCHUM researcher Alex Parker, who has provided representative C. elegans models of ALS, and with a company in British Columbia, to exploit this molecular mechanism to identify small molecules to maintain G3BP1 and thus prevent neurodegeneration.

Basic research in tune with the clinic

Every year, approximately 100 patients are monitored at the CHUM and, if they are eligible, can enter one of the clinical trials conducted at the CRCHUM, particularly in the Unit for Innovative Therapies (UIT). There, patients are offered the most advanced treatment options in neurology, including drugs being used for the first time in humans.

“About a year and a half ago, I was able to start an autopsy program. This has allowed us to collect and store high quality patient tissue samples. The team led by my colleague, Dr. Alexandre Prat, helps us with this initiative. We have already had a few patients donate their brains so that we better understand the disease process,” states Dr. Geneviève Matte, director of the CHUM ALS Clinic and president of the Canadian ALS Research Network.

This biobank is crucial for the progress of Christine Vande Velde’s work because it allows her to validate the mechanisms discovered in the laboratory on patient tissues.

“I believe that we have succeeded in establishing a cohesive link between the laboratory and the clinic.” The complementary nature of the two researchers’ work is particularly evident in the field of their current research.

Targeting environment and financing

Thanks to a recent grant from the Canadian Institutes of Health Research, Christine Vande Velde’s team is investigating how motor neurons are affected by environmental stress. For her part, Dr. Matte is investigating the links between copper exposure and the development of ALS in collaboration with Susan Gaskin, a researcher at McGill University. She and Alex Parker are also setting up a clinical trial for a compound that is showing beneficial effects in an animal model of ALS.

On a day-to-day basis, says Dr. Matte, “advancing knowledge and giving hope to our patients is what motivates us. But it takes more than passion! Funding for basic and clinical research is the lifeblood of our project. Unfortunately, we are sorely in need of it.”

Do you wish to support their research? Make a donation to the Fondation du CHUM specifying that you would like it to be used to advance ALS research projects.

About the research

Funding was provided by the Canadian Institutes of Health Research, the ALS Society of Canada, Brain Canada, the ALS Association (United States) and the Target ALS/Frontotemporal Degeneration Association (United States).