Biochemical Analysis and Structural Determination of LRRK2 with Kinase Inhibitors

Study Rationale:                   
Although pharmacological and surgical treatments are available to manage the symptoms of Parkinson’s disease (PD), none yet can slow down or stop the course of the disease. We propose to target a protein (LRRK2) that is altered in PD to modify the disease process.

Hypothesis:
We seek to elucidate the mechanism by which LRRK2 may be inhibited to stop the progression of PD.

Study Design:
We propose to determine the structures of LRRK2, both wild-type (normal) and mutants, through x-ray crystallography and cryo-electron microscopy (cryo-EM), especially of any regions containing the kinase domain in complex with small molecule inhibitors. The study is designed to visualize how small molecule inhibitors bind to the protein and exert their effects.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
The success of the project will lead to structural templates for mechanism-based optimization of known LRRK2 inhibitors to achieve efficacy and specificity, with high and immediate impact on PD research and therapeutic development.

Next Steps for Development:
Optimized LRRK2 inhibitors will be tested in clinical models of PD with either wild-type or mutant LRRK2.