Michael J. Fox Foundation for Parkinson’s Research

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.