Alterations in the gene LRRK2 are associated with inherited forms of Parkinson's disease (PD). Although it remains unclear why changes in LRRK2 cause the disease, the majority of research on LRRK2 has concentrated on why LRRK2 may influence survival of brain cells which usually are lost in PD. However, LRRK2 is also produced in other areas of the brain, including those which respond to PD treatments, and those with LRRK2 mutations may have different responses to therapy compared to those with different types of PD.
We hypothesize that LRRK2 influences the function of a brain region called the striatum, which is the key region affected by dopamine drugs in PD, resulting in altered responses to PD therapies.
We will examine the role of LRRK2 in dyskinesia, a debilitating abnormal movement which is a common complication of PD treatment, by first creating dyskinesia with standard medications in pre-clinical models with either normal or abnormal LRRK2 levels. We will then use modified viruses to transfer a genetic sequence into the area of the brain which responds to dopamine to block production of LRRK2 and to determine if reducing LRRK2 in this brain region may influence the development of this treatment complication.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Since LRRK2 is the most common single gene altered in inherited forms of PD, it may play a critical role in pathways that influence PD in general. Our results should identify new functions for this critical gene beyond simply influencing cell survival, which could lead to improved treatments with reduced side effects.
Next Steps for Development:
The results of our study will support development of gene or drug therapies targeting LRRK2 to improve symptoms and reduce complications of PD treatments and may provide a basis for more extensive studies exploring the relationship between LRRK2 and responses to therapies.