LRRK2 Activity and Dyskinesia

Promising Outcomes of Original Grant:
Leucine-rich repeat kinase 2 (LRRK2) is the greatest known genetic contributor to Parkinson's disease (PD). We previously studied the role of LRRK2 in the development of drug-induced involuntary movements called dyskinesia. We initially hypothesized that increased LRRK2 activity could worsen dyskinesia, but results from our pre-clinical study showed that increased production of LRRK2 has no effect on dyskinesia. Contrarily, lower LRRK2 production within a brain region called striatum ¬-- the main target of dopamine in the brain -- increased dyskinesias in pre-clinical models of Parkinson's. This suggests that LRRK2 production may be a key regulator of dyskinesia induced by dopamine-based drug therapy for PD.

Objectives for Supplemental Investigation:
One important function of LRRK2 is to modify proteins in a process known as a kinase activity. Increased LRRK2 kinase activity has been associated with the loss of dopamine-producing cells in Parkinson's, so there has been much interest in developing drugs that block this activity without aggravating dyskinesia.

One of the drugs that can block LRRK2 kinase activity is MLi-2. We plan to study the effects of MLi-2 on dyskinesia in pre-clinical models of Parkinson's with and without LRRK2-associated PD.

Importance of This Research for the Development of a New PD Therapy:
Increased LRRK2 kinase activity may play a role in Parkinson's cell death, so there has been considerable effort to develop inhibitors that may regulate LRRK2 activity and protect cells from disease. We found that the loss of LRRK2 can worsen dyskinesia caused by a standard drug therapy for Parkinson's. Through our studies, we will determine whether treatment with LRRK2 kinase inhibitors may aggravate dyskinesia. If so, such treatment could worsen the response to standard drug treatment despite its potential to slow Parkinson's disease progression.