Study Rationale:
Changes in the gene GBA that cause malfunction of a protein known as glucocerebrosidase (GCase) are found in about 10 percent of Parkinson’s disease (PD) patients. Even those PD patients who do not have a malfunctioning GBA gene have lower levels of the GCase protein in the brain. Malfunctioning of the GCase protein is also known to contribute to alpha-synuclein toxicity. And increasing GCase protein levels in PD models protects them against disease. As a result, there is high interest in identifying molecules that can increase GCase activity, since these could advance to become drugs that block PD.
Hypothesis:
We aim to find molecules that can increase GCase levels in living cells with the expectation that these could to lead to promising compounds that could be used to help combat Parkinson’s disease.
Study Design:
We have invented a new way to rapidly test many thousands of compounds to quickly identify those that can increase GCase in living cells. By performing this rapid testing of compounds, we can identify those that show promise and then test them in different models to confirm they are increase GCase activity.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Promising compounds found in our rapid assays, and confirmed as increasing GCase levels in cells, will open the door to developing these molecules to get them to increase GCase within brain. These compounds could drive forward the goal of creating a disease-modifying therapy for PD.
Next Steps for Development:
The most promising compounds would be improved using chemistry to have improved properties. To realize this goal, we would seek out companies with expertise in Parkinson’s disease to partner and rapidly advance suitable compounds into clinical testing.