Grant: Project Grant

Every cell is like a busy city: it has to coordinate information flow, perform thousands of different tasks, and move materials, like fats and proteins, to where they are needed. Like cities, cells have a complex internal transportation system that controls traffic. This system works well most of the time, but can get disrupted, and persistent disruptions can cause dysfunction and disease. This project focuses on an important part of this cellular transportation system called "retromer". Problems with retromer cause neurological disorders such as Parkinson's and Alzheimer's disease, but to develop effective treatments for these conditions, we first need to understand the fundamental causes of disease. Many of the traffic signals and pathways linked to human disease are also found in yeast, a simple one-celled organism. Studying retromer in yeast allows us to use different genome-wide technologies to uncover pathways and machinery on a very large scale and allows us to make discoveries that would be difficult or impossible in complex organisms. In fact, retromer was first discovered in yeast, and many important discoveries about retromer are still being made in this cell system. Recently, we discovered that a family of "VPS9-like" proteins regulates retromer assembly in yeast. One of these proteins, called "VARP", was also found to be important for retromer function in human cells. This gives us the unparalleled opportunity to use yeast to study VARP and establish exactly how it regulates retromer. Once we have made discoveries in yeast, we can transfer this knowledge to the study of cells from mice or humans to test if increasing VARP function can overcome the retromer defects seen in Parkinson's or Alzheimer's disease. In the longer term, our research is expected to identify new drug targets that will help in the development of new treatments for these neurodegenerative disorders.