Study Rationale:
Genetic studies have demonstrated that the GBA1 gene encoding beta-glucocerebrosidase (GCase) (an enzyme that breaks down fats) is a major risk factor for Parkinson's disease (PD). Moreover, patients with Gaucher's disease (in which fatty substances build up in the body) due to GBA1 loss-of-function mutations have an increased risk of developing PD, providing compelling evidence that loss of GCase function is linked to PD pathogenesis.
Hypothesis:
We will develop novel GCase modulators that increase GCase activity, improve lysosome (parts of the cell that contain GCase) function and decrease lipids, thus reducing alpha-synuclein levels and the clumping and formation of toxic fibrils in PD.
Study Design:
We plan to screen a drug-like compound library using a novel binding fluorescence assay (test) we recently developed. We also plan to conduct a screen of commercial drug-like databases using our recently resolved crystal structure of GCase to verify hit compounds using enzyme activity and cell-based assays. By combining the results from this screen with our previous structure-activity relationship studies and structure-based drug design, we will develop novel GCase modulators with potent binding affinity and better drug-like characteristics and we will then test them in cell assays.
Impact on Diagnosis/Treatment of Parkinson's disease:
The development of GCase modulators will prevent and/or delay the onset and progression of PD and provide a new treatment option.
Next Steps for Development:
We will evaluate GCase modulator candidates in pre-clinical models. Ultimately, we plan to identify novel small molecules, which will be critical to accelerate the development of GCase modulators to target PD pathogenesis.