Chemical biology probes to monitor glucocerebrosidase activity in fixed cells and tissues

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People generally have two copies of each gene. A mutation in one of the many disease-related genes that humans have can increase the risk of developing disease. But having a mutation in one of these disease-related genes does not always mean that a person will get the disease. Such a case is known to occur in Parkinson Disease (PD) where the most common hereditary factor contributing to PD are mutations in the gene called GBA. This gene codes for the protein glucocerebrosidase (GCase) that cuts glucose off from a sugar-modified fat molecule that is especially abundant in brain. Even though people with this mutation are much more likely to get PD earlier on and have more severe symptoms, not all people who have a mutation in the GBA gene do develop PD. This has led people to hypothesize that there are other genes that interact with GBA and either increase or decrease the chance of getting PD. This is known to occur for other diseases where mutations in various genes can influence the likelihood of developing a specific disease through what is known as a genetic interaction. There is accordingly high interest in identifying genes that interact with GBA and then understanding how they might influence GCase function. Indeed, little is known about how GCase is regulated within cells but such fundamental information could help better understand the regulation of this protein. In this proposal we aim to exploit our recent advances in chemical biology tools that enable directly watching the activity of GCase protein in living cells. In addition, we will chemically synthesize new probe molecules that enable measuring the activity of this enzyme in new ways. Ultimately, we will use these chemical tools to identify genes that interact with GBA using state of the art screening methods. In this way we will get a basic understanding of how such genes could regulate GCase. Such knowledge could be exploited by pharmaceutical companies to create new drugs that could benefit PD patients in Canada and around the world. Because PD is the second most common neurodegenerative disease, and there is no treatment that slows progression of PD, there is a great need to new insights that could be exploited to create new medicines.