Study Rationale:
Mutations in leucine-rich repeat kinase-2 (LRRK2) are the greatest known genetic cause of Parkinson’s disease (PD). LRRK2 inhibitors may represent a new type of disease-modifying therapies, as several lines of evidence support the beneficial effects of this class of drugs. In this study, we will investigate the molecular and cellular effects of LRRK2 kinase inhibition in neurons and microglia (immune cells in the brain). This research represents a crucial step in the development of safe and effective LRRK2 kinase inhibitors as PD therapies.
Hypothesis:
We aim to provide insight into the molecular and cellular effects of LRRK2 kinase inhibition in neurons and microglia.
Study Design:
Using different LRRK2 kinase inhibitors and different cell culture conditions, we will study how the changes seen with LRRK2 kinase inhibitors are regulated and how they relate to LRRK2 modification in neurons and during microglial activation. We also aim to understand the effects of LRRK2 kinase inhibition on both neurons and microglia, given the importance of microglial activation in neuronal cell death in PD. By combining these results, we will be able to correlate inhibitor-induced cellular and molecular changes related to LRRK2 function and protein levels.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
This study will provide important data that can help evaluate whether reducing LRRK2 levels provides beneficial or harmful effects on LRRK2 kinase inhibition and will inform how we can control LRRK2 protein stability. Moreover, the assays (tools for analysis) developed may be applied to future drug testing and may further increase our knowledge of new therapies for PD.
Next Steps for Development:
These findings will provide clarification on whether LRRK2 protein stability should be controlled and which factors can be used to further develop safe and effective LRRK2 kinase inhibitors and/or redirect current therapeutic (LRRK2) PD strategies.