The project will investigate Cyclin-G associated kinase (GAK), a candidate risk gene for Parkinson’s disease (PD), based on genome-wide association studies (GWAS). GAK plays an important role in LRRK2 (a well-characterized gene associated with PD) dysfunction. However, current data do not indicate which aspects of GAK function are required for LRRK2 effects.
The aim of the proposed experiments is to establish whether endogenous GAK kinase (protein regulation) activity is important in mediating the effects of LRRK2 in cells.
A series of assays (analytic tests) in cell culture models (screens and mechanistic models) will be performed using small molecule, drug-like and selective GAK inhibitors.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If LRRK2 inhibitors do not move forward into clinical trials, GAK inhibitors might be considered as an alternative therapeutic approach for PD.
Next Steps for Development:
These experiments will determine whether GAK inhibitors should be pursued as an alternative strategy to inhibit LRRK2 function outside of direct inhibition of LRRK2. If successful, the most promising compounds will be tested further in pre-clinical models.