Aperçu du projet

Amyotrophic lateral sclerosis (ALS) is a fatal disease involving the gradual death of motor neurons. Motor neurons control the body’s movement. As such, their loss leads to muscle weakness, paralysis, and eventually death. Unfortunately, there is no cure or treatments for those living with ALS, in part because the cause of the disease is not well understood. However, recent findings from a familial form of ALS (ALS-FUS) suggests that mutations in a protein called Fused in Sarcoma (FUS), is involved in causing the disease. In particular, our research suggests that FUS has a critical function in maintaining the health of motor neurons and that the activity of FUS can be controlled by nutrient (i.e. fats) availability. Part of maintaining healthy motor neurons is through the conversion of nutrients into energy. Our research will determine: 1) The role of FUS and ALS-FUS mutants in controlling the use of nutrients for the production of energy; and 2) the therapeutic efficacy of gene-editing an ALS-FUS mutation (R521G) on the restoration of healthy motor neurons. In our ALS-FUS mouse model, we will examine the effects of high fat diets on the ability of these mice to regulate the production of energy. We will also determine how ALS-FUS mutants are disrupting the normal production of energy in these mice. Seminal findings in our study will be confirmed in post-mortem human brain and spinal cord tissue samples in collaboration with the ALS-tissue repository. Finally, we will take a therapeutic approach to treating ALS-FUS mice using the gene-editing technology, CRISPR/Cas9. We will inject CRISPR/Cas9 virus into ALS-FUS mice and test the impact of this therapy on saving the motor neurons. The findings from our study will advance our understanding of how FUS controls energy production and provide preclinical validation of gene-editing as a treatment strategy for ALS.