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.
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.
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.