Grant: Project Grant

In Canada, the annual cost to care for individuals with neurodegenerative diseases is over $10.4 billion. There are no therapeutic interventions that sufficiently prevent or treat neurodegenerative diseases because the cause of neurodegeneration is complex and not well understood. Recent studies have shown brain cells of individuals with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), accumulate small globules (droplets) of lipid (fat), indicating abnormal metabolism of fatty acids are involved in disease toxicity. Our research project aims to investigate how pathways of lipid metabolism are disrupted in ALS, using our mouse model of familial ALS due to mutations in the FUS gene. ALS is a fatal neurodegenerative disease caused by the dysfunction and death of neurons in the brain and spinal cord responsible for voluntary movement. Neurons important for cognition and memory can also be affected. ALS-FUS mice have defects in both motor function and cognition. Importantly, we have observed aberrant accumulation of lipid droplets and toxic lipid by products in specific brain regions and neural cell types that correspond with impaired brain function, including both neurons and astrocytes. We will determine any specific effect of FUS variants on how fatty acids are metabolized and expression of the proteins involved, as well as testing more general involvement in pathogenesis using models of other forms of ALS. The results will help us understand the importance of lipid dysregulation in ALS and point to potential new targets for intervention.