Elucidating the role of stress granules dynamics in the pathogenesis of ALS
Aperçu du projet
The lifetime risk of developing amyotrophic lateral sclerosis (ALS) is approximately 1 in 350 for men and 1 in 440 for women, making it the most common adult-onset motor neuron disease. There is no cure and poor prognosis for this devastating neurodegenerative disease, resulting in increased mortality and morbidity. With the prevalence of ALS occurring in 5 in 100,00 and therapeutic strategies largely focused on palliative care, more research is necessary to understand the mechanism of disease to develop a more tailored approach to treatment and cure. ALS causes the selective degeneration of motor neurons in the brain and the spinal cord, however the contribution of genetic abnormalities, termed mutations, to disease pathology is not clear. Many mutations causing ALS involve genes that produce proteins important for stress granule production and clearance/disassembly. Stress granules are assemblies of messenger RNA and RNA-binding proteins in response to stress. If the cell can re-establish normal conditions, stress granules will disassemble or be cleared by autophagy. The current theory states that mutations in stress granule-related proteins result in the production of more stable stress granule structures that cannot disassemble or be cleared, or that mutations that cause disruptions in autophagy resulting in more persistent stress granule structures. Therefore, our research will attempt to: 1) examine ALS-associated genes for their function in stress granule dynamics, autophagy and TDP-43 mislocalization using high-throughput confocal microscopy, 2) validate genes producing significant stress granule, TDP-43 or autophagy phenotypes in iPSC-derived motor neurons, 3) investigate the mechanism of how one gene candidate directly contributes to the evolution of disease in transgenic mouse models. By systematically evaluating each gene in key disease processes, I can elucidate novel targets for ALS therapeutics, potentially slowing disease progression, reversing its destruction, and increasing the likelihood of patient survival.
Chef d'équipe
Charlotte Manser , University of Ottawa
Partenaire et Donateurs
ALS Society of Canada