Project 451362

Inside each of our cells are a number of specialized compartments called organelles that perform different tasks. These compartments are not simply floating around, but are linked together at "membrane contact sites". Contact sites have an important role in transporting nutrients, lipids and proteins from one compartment to another. When this transport is disrupted, disease can occur. Our proposed research focuses on a family of VPS13 proteins that act a bit like a firehose to rapidly transport large numbers of lipid molecules from one membrane to another. Mutations in the four different VPS13 proteins present in humans cause different neurodegenerative diseases, including Parkinson's and autism. Evidence suggests that these human VPS13 proteins localize to different membrane contact sites which may explain why mutations in these four proteins result in distinct neurological disorders. We would like to understand how VPS13 proteins are sent to contact sites and how mutations in these proteins can change their location in cells resulting in neurodegeneration. We have found that the related yeast Vps13 protein is sent to different contact sites with the help of adaptors. These adaptors bind Vps13 at a site that is conserved in human VPS13 proteins. We have also recently discovered new proteins that resemble VPS13 and may transport lipids in a similar manner. Our research will identify the proteins needed for VPS13 recruitment and function at different contact sites in yeast and human cells, and clarify the role of the new VPS13-like protein at contact sites. Understanding how VPS13 proteins are localized within the cell will give us a better understanding of the disease mechanisms associated with each disorder and give us insights into potential therapeutic interventions.