LRRK2 Activity and Dyskinesia Supplement

Promising Outcomes of Original Grant:
Our preliminary funding supported exploration of the role of striatal LRRK2 in the development of levodopa-induced dyskinesia (LID). We found that inhibiting LRRK2 in the dorsal striatum of 6OHDA lesioned parkinsonian models significantly worsens LID compared to controls. One important function of LRRK2 is its kinase activity, which is increased in the most common PD-associated mutation, G2019S. Interestingly, we found that knock-in (KI) mice carrying the G2019S LRRK2 mutation have a significant reduction in LID severity compared to wild type littermates. This suggests that endogenous striatal LRRK2 may be a key regulator of the dyskinesia response to dopaminergic pharmacotherapy.

Objectives for Supplemental Investigation:        
It is possible that loss of LRRK2 kinase activity could be responsible for increased LID following LRRK2 knockdown. Since disease-modifying benefits of LRRK2 kinase inhibitors would likely require chronic treatment concurrent with dopamine replacement therapy, we hypothesized that chronic administration of LRRK2 inhibitors with levodopa worsens LID in Parkinson’s models. To determine the effect of therapeutic inhibition of LRRK2 activity, we will measure LID in models chronically treated with the selective LRRK2 kinase inhibitor MLi-2 (or vehicle). LID severity will be quantified in our cohort of 6OHDA lesioned wild type and G2019S LRRK2 KI mice treated chronically for 3 weeks with a combination of levodopa and MLi-2 to mimic the human PD condition.

Importance of This Research for the Development of a New PD Therapy:             
Increased LRRK2 kinase activity has been associated with loss of dopamine neurons; therefore, there has been considerable effort to develop selective inhibitors as treatment for PD. In our original study, we found that reduction in endogenous LRRK2 levels worsens LID following levodopa administration in PD models. This suggests that it is critical to determine whether chronic treatment with LRRK2 kinase inhibitors may have unintended consequences on responses to dopamine replacement therapy in PD patients, since disease-modifying benefits would likely require chronic treatment concurrent with dopaminergic pharmacotherapy. Upon completion of these studies, we will have generated critical data to determine the influence of LRRK2 activity on responses to therapy following dopamine denervation, which could lead to novel approaches to treating LID as well as further investigations into the role of LRRK2 as a mediator of striatal function.