Measuring LRRK2-Mediated Rab Protein in Parkinson’s Disease

Study Rationale: 
The discovery of LRRK2 (Leucine rich repeat kinase 2) recently as a gene that causes Parkinson’s disease has provided considerable insights into the development of both familial and non-familial forms of the disease. Recent work has identified a subgroup of proteins called Rab GTPase as directly linked to LRRK2 and associated with Parkinson’s.

Hypothesis: 
In this project, we will investigate the roles of Asian LRRK2 variants (G2385R, R1628P and S1647T) in a chemical process called phosphorylation in Rab proteins in the immune cells from Parkinson’s patients and control volunteers.

Study Design: 
In collaboration with The Michael J Fox Foundation, Dr. Alessi and Dr. Mann are in the process of developing an analytical chemistry test called a mass spec assay to detect all the major Rab proteins in human biosamples and are generating antibodies to multiple Rabs. We will measure LRRK2 activity in the Asian variant cohort in comparison to the G2019S cohort. Our immediate goal is to recruit patients carrying the Asian LRRK2 variants (G2385R, R1628P and S1647T) and collect blood immune cells and bank them for LRRK2 and Rab testing.
    
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our findings will suggest that it may be possible to find compounds to suppress LRRK2 activity. Moreover, patients with LRRK2 risk variant Parkinson’s might benefit from LRRK2 inhibitor treatments that have entered clinical trials in humans.

Next Steps for Development:
We will test the effect of LRRK2 inhibitors on Rab phosphorylation by LRRK2 Asian variants.