LRRK2 Mutations and the Development of Therapeutic LRRK2 Inhibitors

Study Rationale:
Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein can cause an inherited form of Parkinson's disease (PD). Understanding how these mutations cause PD is complicated, as they have several effects on the LRRK2 protein. This project aims to use new models to separate the effects of LRRK2 mutations and study them in isolation. This work may help describe how LRRK2 mutations cause Parkinson's.

Hypothesis:
Our study aims to determine how the specific loss of LRRK2 affects alpha-synuclein
(a protein that is associated with PD) pathology and the progression of PD.

Study Design:
This study will investigate pre-clinical models in which LRRK2 can no longer be altered and how they respond to an experimental Parkinson's disease challenge. Models will be evaluated over time for any PD symptoms and brain tissue will be analyzed for PD pathology.

Impact on Diagnosis/Treatment of Parkinson's Disease:
LRRK2 mutations are a common cause of an inherited form of PD and LRRK2 dysfunction may contribute to idiopathic Parkinson's (no known cause). Understanding how LRRK2 mutations cause PD may help develop drugs to stop the mechanism disrupted by mutations.

Next Steps for Development:
This study will help to rule in or rule out the involvement of LRRK2 changes in PD progression. If ruled in, further work will be required to understand the mechanisms involved.