Study Rationale:
Leucine-rich repeat kinase 2 (LRRK2) is the greatest known genetic contributor to Parkinson's disease (PD). One important function of LRRK2 is to modify itself and proteins called Rab GTPases in a process known as a kinase activity. Parkinson's-linked mutations (changes) in the LRRK2 gene enhance the kinase activity of this protein, making this activity a possible therapeutic target in PD. There are several existing drugs that can be used to inhibit LRRK2, i.e., suppress its activity, in the brain. Self- and protein modifications bone by LRRK2 are reversed when it is inhibited. Therefore, we can monitor these modifications to determine how efficiently LRRK2 is inhibited in the brain.
Hypothesis:
In this study, we will compare modifications of LRRK2 and Rab GTPases to investigate the response to inhibition throughout the body and subsequently explore effects of long-term treatment with LRRK2 inhibitors.
Study Design:
We will use pre-clinical models of LRRK2-associated Parkinson's to study consequences of LRRK2 inhibition. Our study is designed to include three stages. During the first stage, we will use new tools developed by The Michael J. Fox Foundation to detect modifications of Rab GTPases and LRRK2 and characterize their efficacy in pre-clinical models. We will use these to study a connection between the dose of an inhibitor drug and the effect of the drug. We will also compare modifications in the brain to those in the kidneys and the lungs. During the second stage of the study, we will investigate how modifications of LRRK2 and Rab GTPases get removed and added again. During the final stage of the study, we will investigate the effects of long-term LRRK2 inhibition focusing on these modifications but also evaluating global protein changes in different tissues.
Impact on Diagnosis/Treatment of Parkinson's disease:
This study will provide further insight into the role of protein modifications as indicators of LRRK2 kinase activity and the possibility of using these modifications in the clinical practice as biomarkers (objective measures) of Parkinson's disease. Changes in LRRK2 kinase activity may serve as biomarkers useful in diagnosing PD before the onset of symptoms. LRRK2 and Rab GTPase modifications could also be used to monitor the efficacy of inhibitor drugs.
Next Steps for Development:
Once we verify the usefulness of LRRK2 and Rab GTPase modification in predicting LRRK2 activity in different tissues, we could confirm our findings in human tissue samples. Recent studies show that modification of Rab GTPases is a promising tool in monitoring LRRK2 activity in human blood cells. Complementary to this approach, self-modification of LRRK2 can be used as a direct way to measure its activity. Therefore, the use of LRRK2 self-modification in clinics should be explored.