A previously unknown link between the immune system and the death of motor neurons in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, has been discovered by scientists at the CHUM Research Centre and the University of Montreal. The finding paves the way to a whole new approach for finding a drug that can cure or at least slow the progression of such neurodegenerative diseases as ALS, Alzheimer's, Parkinson's and Huntington's diseases.
The study, published today in Nature Communications, shows that the immune system in the animal model C. elegans, a tiny 1 mm-long roundworm, plays a critical role in the development of ALS. “An imbalance of the immune system can contribute to the destruction of motor neurons and trigger the disease,” said Alex Parker, CRCHUM researcher and Associate Professor in the Department of Neuroscience at the University of Montreal.
Amyotrophic lateral sclerosis is a neuromuscular disease that attacks neurons and the spinal cord. Those affected gradually become paralyzed and typically die less than five years after the onset of symptoms. No effective remedy currently exists for this devastating affliction. Riluzole, the only approved medication only extends the patient's life by a few months.
More than a dozen genes are related to ALS. If a mutation occurs in one of them, the person develops the disease. Scientists introduced a mutated human gene (TDP-43 or FUS) into C. elegans, a nematode worm widely used for genetic experiments. The worms became paralyzed within about 10 days. The challenge was to find a way of saving them from certain death. “We had the idea of modifying another gene—tir-1—known for its role in the immune system,” said Julie Veriepe, lead investigator and doctoral student under the supervision of Alex Parker. Results were remarkable. “Worms with an immune deficit resulting from the tir-1 gene's mutation were in better health and suffered far less paralysis,” she added.
This study highlights a never previously suspected mechanism: even if the C. elegans worm has a very rudimentary immune system, that system triggers a misguided attack against the worm's own neurons. “The worm thinks it has a viral or bacterial infection and launches an immune response. But the reaction is toxic and destroys the animal's motor neurons,” Alex Parker explained.
Is the same scenario at work with people? Most likely. The human equivalent of the tir-1 gene—
SARM1—has proved crucial to the nervous system's integrity. Researchers think the signalling pathway is identical for all genes associated with ALS. This makes the TIR-1 protein (or SARM1 in humans) an excellent therapeutic target for development of a medication. SARM1 is particularly important because it is part of the well-known kinase activation process, which can be blocked by existing drugs.
Alex Parker's team is already actively testing drugs that have been previously approved by the US Food and Drug Administration for treatment of such disorders as rheumatoid arthritis, to see if they work with ALS. Obstacles still remain, however, before finding a remedy for curing or slowing the progression of amyotrophic lateral sclerosis. “In our studies with worms, we know the animal is sick because we caused the disease. This allows us to administer treatment very early in the worm's life. But ALS is a disease of aging, which usually appears in humans around the age of 55. We do not know if a potential medication will prove effective if it is only given after appearance of symptoms. But we have clearly demonstrated that blocking this key protein curbs the disease's progress in this worm,” Alex Parker concluded.
About the study
The study "Neurodegeneration in C. elegans models of ALS requires TIR-1 / Sarm1 immune activation pathways in neurons" was published in Nature Communications. All authors are affiliated with the CHUM Research Centre and the University of Montreal: Julie Veriepe, Lucresse Fossouo and J. Alex Parker. This research was financially supported by an ALS Canada-Brain Canada Discovery Grant, and the Canadian Institutes of Health Research (CIHR). For more information, see the study online: www.nature.com/ncomms/2015/150610/ncomms8319/full/ncomms8319.html
About the CRCHUM
The Université de Montréal Hospital Research Centre (CRCHUM) improves the health of adults through a high-quality academic research continuum which, by improving our understanding of etiological and pathogenic mechanisms, fosters the development, implementation, and assessment of new preventive, diagnostic and therapeutic strategies. The CRCHUM provides a training environment to ensure the development of new generations of researchers committed to research excellence.
About Université de Montréal
Deeply rooted in Montreal and dedicated to its international mission, Université de Montréal ranks among the top 1% of the world’s best universities and is considered the top comprehensive university in the Francophonie. Founded in 1878, UdeM today has 15 faculties and schools, and together with its two affiliated schools, HEC Montréal and Polytechnique Montréal, constitutes the largest centre of higher education and research in Quebec and one of the most important in North America. It has 2,800 professors and researchers and more than 66,000 students.