Study Rationale: Parkinson’s disease (PD) is associated with activating mutations in a protein kinase called LRRK2. In previous studies, we found that regulating LRRK2’s chemical modification by phosphorylation controls the inappropriate activation of the protein. Because LRRK2 phosphorylation is decreased in PD, we propose that enhancing LRRK2 phosphorylation at key sites on the protein will reduce its pathological activity. We have discovered molecules that protect LRRK2 phosphorylation by stabilizing its interaction with an adapter protein called 14-3-3. For this project, we will further develop these novel, phosphorylation-stabilizing compounds to reduce LRRK2 activity and its pathophysiological effects in cells and preclinical PD models.
Hypothesis: 14-3-3 proteins are known to bind to two phosphorylated sites on LRRK2, acting as a cap that prevents dephosphorylation. We therefore hypothesize that stabilizing the interaction between LRRK2 and 14-3-3 will favor the phosphorylated form of LRRK2 and avoid accumulation of the dephosphorylated form that is associated with PD.
Study Design: In the first phase of the study, we will characterize and identify the compounds in our collection that are the most potent and selective at stabilizing LRRK2:14-3-3 interactions. Next, we will confirm that the most promising compounds block LRRK2 activation and functioning in cellular models. Based on the results of these experiments, we will select the specific LRRK2:14-3-3 stabilizers we will administer in preclinical PD models to determine whether these compound can block the PD-related symptoms and pathology.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our LRRK2:14-3-3 stabilizing compounds represent both an alternative strategy to targeting LRRK2 activation and an approach that could potentially complement other treatments that inhibit LRRK2 kinase activity. As a disease-modifying agent, this novel therapeutic is predicted to be effective at all stages of the disease.
Next Steps for Development: At the end of this study, we wish to have at least one compound that reverses LRRK2’s pathophysiological effects in both cellular and preclinical models. This will set the stage for ongoing long-term studies in additional preclinical PD models.