Study Rationale: Genetic mutations that activate LRRK2 are linked to familial Parkinson’s disease (PD). However, no clinically approved inhibitors for LRRK2 currently exist. In this study, we will develop and characterize novel compounds that inhibit either LRRK2 itself or a key component in the signaling pathway that LRRK2 activates. Together, these tools will be used to investigate the mechanism and function of LRRK2 in cells.
Hypothesis: We hypothesize that disrupting LRRK2 function or targeting a key signaling pathway that is overactive in PD may serve as effective strategies to block altered signaling in people with the disorder.
Study Design: As a strategy to disrupt the LRRK2 hyperactivity seen in PD, we will design new compounds that block LRRK2 function or diminish its downstream signaling. We will use a variety of tests to measure how effective these compounds are at limiting the high levels of LRRK2 activity and altered signaling that are associated with the disease state.
Impact on Diagnosis/Treatment of Parkinson’s disease: This study will explore new targeting strategies for blocking the excessive activity of LRRK2, a key underlying mechanism in familial PD progression. If successful, the results will validate new LRRK targets and present a novel strategy for the development of PD therapeutics.
Next Steps for Development: The inhibitors developed in this work may serve as templates for the development of completely novel therapeutic agents in PD. Future preclinical studies will further establish the efficacy and feasibility of this approach.