Researchers Discover Immune System Plays a Critical Role in ALS Development

Researchers at CRCHUM and the University of Montreal in Canada discovered a previously unknown link between amyotrophic lateral sclerosis (ALS) neurodegeneration and the immune system. The study was recently published in the journal Nature Communications and is entitled “Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons”.

ALS is a progressive neurodegenerative disease characterized by the gradual degeneration and atrophy of motor neurons in the brain and spinal cord, responsible for controlling essential voluntary muscles, such as the ones related to movement, speaking, eating, and even breathing. ALS patients may become totally paralyzed and the majority succumb to the disease due to respiratory failure within two to five years post diagnosis. It is estimated that more than 300,000 Americans suffer from ALS and there is currently no cure.

Researchers reported the discovery of a link between the death of motor neurons in ALS and the immune system. Several genes have been reported to be linked to ALS, and if a mutation occurs in one of them, the individual develops the disease.

Using the roundworm Caenorhabditis elegans as a model, researchers introduced into the animal a mutated human gene that promotes ALS development. The team found that the animals became paralyzed within 10 days. Their goal was then to halt or reverse this phenotype and avoid the worm’s death.

“We had the idea of modifying another gene – tir-1 – known for its role in the immune system,” said the study’s lead author Julie Veriepe in a news release. Remarkably, the team found that “Worms with an immune deficit resulting from the tir-1 gene’s mutation were in better health and suffered far less paralysis,” suggesting that tir-1 dysfunction suppressed motor neuron degeneration in this ALS model.

The findings led the team to suggest that the immune system plays a critical role in ALS development. “An imbalance of the immune system can contribute to the destruction of motor neurons and trigger the disease,” explained the study’s senior author Dr. Alex Parker. “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,”

Researchers suggest that the immune system reacts to the presence of mutant proteins through a pathogen resistance response that is ultimately harmful for the body leading to progressive neurodegeneration. The team believes that these findings are also applicable to humans. SARM1 is the human equivalent of TIR-1, and it has been proven critical for the nervous system’s integrity.

The research team concluded that TIR-1/SARM1 protein is a promising therapeutic target to treat or at least slow ALS disease progression, and that this pathway is most likely triggered by all mutated genes linked to ALS. The team is currently testing drugs able to block this pathway that have been approved by the U.S. Food and Drug Administration for the treatment of other disorders like rheumatoid arthritis.

The authors are, however, cautious when referring to an effective ALS treatment strategy. “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 [TIR-1/SARM1] curbs the disease’s progress in this worm,” concluded Dr. Parker.