Investigation of Small Molecules to Rescue Lysosomal and GBA Deficiencies in GBA PD

Study Rationale:
Individuals with mutations in the GBA gene have a higher risk of Parkinson’s disease (PD) and another genetic condition: Gaucher disease. GBA mutations lower activity of the protein glucocerebrosidase (GCase), which plays a role in the cell’s disposal and recycling centers residing in lysosomes. In PD, lower GCase activity impacts cells’ ability to eliminate clumping of the protein alpha-synuclein, which is detrimental to cells. We will study potential therapies that aim to protect cells from this process.

Hypothesis:
Small molecules that increase GCase activity and improve lysosomal function in Gaucher disease samples will have disease-modifying potential in GBA PD.

Study Design:
From a high-throughput screen on Gaucher patient-derived cells, we identified small molecule compounds 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 expression in fibroblasts from GBA PD patients. The compounds will be used to probe changes in protein expression within the cell’s

Impact on Diagnosis/Treatment of Parkinson’s Disease:
A disease-modifying treatment for GBA PD would be a significant advancement for patients. In addition, understanding how our compounds increase GCase activity and improve lysosomal function in GBA PD has potential to identify new targets for drug discovery.

Next Steps for Development:
Compounds will be advanced into GBA PD models to evaluate GCase activity and reduced alpha-synuclein protein levels. The compounds’ drug-like properties will be optimized by medicinal chemistry.