Grant: CIHR Fellowship

Proteins are the critical bio-machines that safeguard a cell's survival. They coordinate an array of critical cellular processes including providing energy, monitoring for signs of damage and facilitating crucial biological reactions. However, the DNA that encodes these molecular machines can often be mutated. Such mutations can cause proteins to become misshapen and toxic. This commonly occurs in neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's diseases as well as in genetic diseases like cystic fibrosis. Interestingly, mutations are most likely to alter proteins by changing the shape and assembly of these critical molecules. Indeed, a number of rare genetic diseases are thought to be caused by proteins changing shape or not taking on the appropriate shape at all. To prevent error-prone proteins from accumulating, the cell has a system to cull and recycle them. This crucial quality control pathway utilizes a distinct molecular tag, called ubiquitin, to triage these misfolded proteins. Ubiquitin can decorate proteins in unique ways to tag them for destruction or quarantine. This molecular signal has already been shown to be key in familial Parkinson's disease and is associated with many other degenerative conditions. Understanding the biology of how ubiquitin labels defective proteins and how we can tune this process will allow for new therapeutic targets to be identified in rare genetic diseases. This project aims to understand which players are key to the destruction of errant proteins, how they triage damaged proteins and how this can be applied to new treatments for rare diseases. This project will use cutting edge technologies to visualize this process in live cells and provide a new way to screen and identify new target genes that can turn back the clock on these aging and defective proteins.