Study Rationale: Mutations in GBA1, the gene that encodes the enzyme glucocerebrosidase (GCase), are among the most common genetic risk factor for the development of Parkinson’s disease (PD). GCase resides in lysosomes, and alterations in its activity lead to a buildup of lipids and alpha-synuclein. In this project, we will characterize the lipids that accumulate in the absence of GCase activity, molecules that could be potential biomarkers for PD.
Hypothesis: We hypothesize that lack of glucocerebrosidase activity in lysosomes leads to the accumulation of lipids that have a glucose sugar attached, a chemical group that would normally be cleaved by GCase. We further predict that this glucose modification disrupts the function of these lipids in the lysosome.
Study Design: We will use biochemical tools to determine the role of glucocerebrosidase in clearing glucose-modified lipids in the lysosome.
Impact on Diagnosis/Treatment of Parkinson’s disease: This work has the potential to identify novel biomarkers for GBA-PD and new therapeutic targets.
Next Steps for Development: The next step would be to develop tools to detect novel lipids in body fluids from individuals with PD.