This grant builds upon the research from a prior grant: Investigation of Small Molecules to Rescue Lysosomal and GBA Deficiencies in GBA PD
Study Rationale: Individuals with mutations in the GBA1 gene encoding the enzyme β-glucocerebrosidase (GCase) have a higher risk of Parkinson’s disease (PD). Gaucher disease, a rare genetic disease also arises from mutations in GBA1. Both diseases show defects in lysosomes, the cell’s disposal and recycling centers, in part because GCase is unavailable to break down cellular waste. In GBA-associated PD, this deficit impacts neurons’ ability to eliminate toxic alpha-synuclein aggregates. This project will define the mechanisms and pathways that connect the loss of GCase activity to an increase in alpha-synuclein, findings that could lead to identification of new targets for disease-modifying therapeutics.
Hypothesis: We hypothesize that the small molecules that have been used to boost GCase activity and improve lysosomal function in Gaucher’s disease will display disease-modifying activity in GBA-associated PD.
Study Design: Using a high-throughput screen on cells derived from people with Gaucher’s disease, we identified small molecules that were able to improve lysosomal function and increase active GCase levels. We will extend our studies to evaluate the ability of our compounds to improve lysosomal function and increase GCase activity in cells from individuals with GBA-associated PD. We will use the compounds to probe changes in protein expression within the cell’s clearance pathway in these cells to determine where they act to produce a beneficial effect.
Impact on Diagnosis/Treatment of Parkinson’s disease: Identification of a disease-modifying treatment would be a significant advancement for for people with GBA-associated PD. Understanding how our compounds increase active GCase and improve lysosomal function in GBA-associated PD has potential to identify new targets for drug discovery.
Next Steps for Development: Compounds will be advanced into preclinical GBA-associated PD models to establish that increasing GCase activity will reduce alpha-synuclein protein accumulation in animals. We will apply medicinal chemistry to optimize our small molecule’s drug-like properties as the first step to develop a disease-modifying treatment for people with GBA-associated PD.