Project 454672

Amyotrophic Lateral Sclerosis (ALS) affects roughly 3000 Canadians, and patients typically die within 2-5 years of diagnosis. Roughly 1000 Canadians die from ALS, and a similar number are diagnosed each year. Multi-system proteinopathy (MSP) is a rare disorder in which patients present with any combination of muscular dystrophy, bone disease, and premature dementia. A recent study determined that approximately 1 of 300,000 people may be affected globally, perhaps an understatement as the study considered a small sample. Numerous mutations in Valosin-containing protein (VCP) lead to MSP, leading to another name, VCP Diseases. VCP mutations have also been causally implicated in ALS. A study of a multi-generational Italian family with ALS discovered mutations of VCP present in patients that were not present in family members without ALS as well as the general population. VCP is an essential protein with numerous functions, many of which are necessary for autophagy. Autophagy is a critical cellular mechanism that clears toxic proteins from within the cell. Autophagy is disrupted in many neurodegenerative diseases, including ALS and MSP. Many autophagy proteins, including VCP, undergo palmitoylation, the reversible addition of a fatty acid. Similar to a postal code and mail, palmitoylation causes proteins to stick to specific subcellular locations. Too much or too little results in lost or mislocalized proteins. We have observed increased palmitoylation of mutant VCP, coupled with impaired autophagy. We hypothesize that palmitoylation of VCP mutants associated with disease is a treatable unifying mechanism for multiple VCP diseases, including MSP and ALS. This study will characterize the role of palmitoylation on mutant VCP function and test potential therapeutics to improve disease outcomes, measured through changes in autophagy and behaviour. This study will identify and develop potential therapeutic strategies to improve disease outcomes in thousands of Canadians.