Genome-wide screen to identify genetic modulators of glucocerebrosidase activity
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Despite PD affecting millions of people worldwide, no disease-modifying treatment is available yet. As the progress of the disease is closely related to aging, improving our knowledge of the mechanisms and factors leading to PD is of great interest. Mutations in the gene GBA, which encodes the enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for PD. The link between GCase and PD however, remains poorly understood. Here, we propose to use a chemical genetic screening approach to identify new genes that affect GCase activity. As a pilot study, we will target known PD-associated genes and evaluate their effects on GCase activity using a new GCase activity-based assay in live cells. A complementary approach using genome-wide screen will be carried out to identify candidate genes in an unbiased way. Candidate genes from these screens will be validated with downstream experiments leading to two valuable outcomes. First, the discovery of new genes that regulate GCase could provide new targets for potential treatments. Second, we expect these findings will uncover new fundamental understanding regarding the mechanisms contributing to PD.