Defective protein translation: a causative pathway in ALS
Project Overview
Amyotrophic lateral sclerosis (ALS) is a nervous system disease that affects nerve cells (motor neurons) connecting muscle with the brain and spinal cord. ALS causes motor neurons to deteriorate and die, leading to muscle control loss. ALS patients lose control of the muscles needed to move, speak, eat, and breathe, and eventually die within 2-5 years of diagnosis. More than 200,000 people around the world and ~3,000 Canadians are living with ALS, with approximately 1,000 Canadians dying from ALS every year. Hence, there is an urgent need to find a cure for this fatal disorder. The reason there is no cure for ALS is that we do not fully understand why it happens. In most ALS patients’ motor neurons, there are clumps of a protein called TDP-43. These clumps interfere with the way cells work, causing a decrease in protein translation, the critical process by which proteins are produced in the body. In the Cashman laboratory, we have grown cells that contain clumps of TDP-43 and are sick. We identified another protein, called RACK1, that seems to be a key target of TDP-43. When we treat cells to reduce the amount of RACK1, TDP-43 clumps are resolved, and the protein translation is restored to normal. We hypothesize that restoring translation in sick neurons containing TDP-43 clumps could restore the health and function of the neurons, and thus be a treatment for ALS. Because our experiments so far were only performed in cells, and not in animals, we still do not know if this pathway is a major driver for TDP-43 toxicity in humans. The first aim of the project is to create transgenic fruit flies as an ALS disease model. Fruit flies are living animals making them much more relevant to human disease biology than a simple cell model. The second aim of the project is to find how TDP-43 clumps reduce translation in living animals and how lowering or adding more RACK1 fixes this problem. The third aim is to validate our hypothesis that translation machinery is getting damaged via RACK1 by getting structural data on ribosomes, the machines that perform protein synthesis. These results will allow scientists to understand precisely how TDP-43 impairs translation – knowledge which is needed for the design of therapies that restore translation in patient neurons.
Principal Investigator
Amrita Verma , University of British Columbia
Partners and Donors
Naomi Azrieli, François Blanc and Family