Using worms to investigate the disease mechanisms of ALS

The project

Alex Parker and his team are focused on developing and using simple models to study brain diseases, specifically ALS. The model system they use is the Caenorhabditis elegans (C. elegans) worm. This small, transparent worm has just 300 neurons, but is a powerful genetic system used by researchers to model neurodegenerative diseases, among others, and to facilitate drug discovery. By using worms that are genetically engineered to display human ALS traits, Alex Parker studies genes that are thought to be associated with ALS to learn how they function in health and disease. In previous studies, The team discovered a link between the immune system and the death of motor neurons in ALS. Their hypothesis was that mutant ALS proteins inappropriately trigger an immune response as well as a neuronal cell death program leading to motor neuron degeneration.

In 2014, the group received an ALS Canada-Brain Canada Discovery Grant to continue this line of enquiry and further examine how this immune response, known as “innate immunity,” is activated and how it causes motor neurons to die. The goal of their project was to investigate the signaling pathway of this degenerative response using C. elegans to provide a roadmap for future investigations of disease mechanisms and therapeutic approaches in vertebrate systems. They identified the TIR-1/Sarm pathway as a key regulator of neurodegeneration associated with mutant proteins and found that blocking the immune response reduced motor neuron degeneration. These key findings were published in the June 2015 edition of Nature Communications. Alex Parker’s team is now investigating if the TIR-1/Sarm pathway regulates motor neuron degeneration in mouse models of ALS (supported by the Muscular Dystrophy Association). This could eventually provide new treatment targets to slow down ALS progression in humans.