Mutations in the LRRK2 gene cause some forms of Parkinson's disease. Studying this gene's effects has provided insight into the physiological processes that lead to genetic and sporadic (i.e., non-genetic) forms of the disease. Teams funded by The Michael J. Fox Foundation are developing tools to measure aspects of LRRK2 activity in human fluid samples. In the study, we will use these tools to examine LRRK2 activity in people with Asian LRRK2 variants (G2385R, R1628P and S1647T).
Our hypothesis is that LRRK2 activity (specifically in Rab phosphorylation) is similar in Asian LRRK2 variants (G2385R, R1628P and S1647T) as compared to people with the previously studied G2019S variant.
In collaboration with MJFF, Dr. Alessi and Dr. Mann are developing a mass spectrometry assay to detect all the major Rab substrates in human biological samples and are generating antibodies to multiple Rabs. We will measure LRRK2 activity in the Asian variant cohort in comparison to the G2019S cohort. Hence, our immediate goal is to recruit patients carrying the Asian LRRK2 variants (G2385R, R1628P and S1647T) and collect peripheral blood immune cells (specifically monocytes and neutrophils) and bank them for the LRRK2 and Rab phosphorylation assay.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Our findings may indicate patients with Asian LRRK2 risk variants for Parkinson's might benefit from LRRK2 inhibitor drugs, which have already entered clinical trials in humans.
Next Steps for Development:
We will test the effect of LRRK2 inhibitor drugs on Rab phosphorylation by LRRK2 Asian variants.