Study Rationale:
Unraveling the role of LRRK2 mutations in disease remains a critical question in Parkinson’s research. The high expression of LRRK2 protein in part of the brain called the striatum indicates that LRRK2 might play a role in striatal neurons. We previously reported that LRRK2 directs striatal activity of a group of enzymes called protein kinase A (PKA) and the specific R1441C mutation on the LRRK2 gene disrupts proper PKA function. Based on these results we propose that our deepening knowledge of how LRRK2 dysregulation of PKA results in Parkinson’s-like symptoms could provide strong rationale for new therapeutic approaches.
Hypothesis:
We aim to determine whether the genetic or pharmacological inhibition of a PKA subunit would lessen R1441C-induced effects as well as whether the dysregulation of the striatal LRRK2-PKA axis is seen in other PD-like models.
Study Design:
We will use viral-mediated RNA interference to knock down the gene encoding the regulatory subunit of PKA within the striatum of LRRK2 mutation and control pre-clinical models. To generalize the importance of those findings to other parkinsonian models, we will determine what the contribution of LRRK2-PKA interaction is in dopamine depletion. In turn, the functionality of the PKA pathway will be determined by behavioral and biochemical assessments.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If LRRK2 and its mutations have a role, at least in some part, in how striatal neurons respond to dopamine stimulation that relies on PKA pathway, then we may be able to pursue this pathway as a therapeutic target.
Next Steps for Development:
Although it is a significant challenge to develop PKA inhibitors that selectively target the striatal neurons, these findings will provide molecular basis for designing potential therapeutics that could inhibit abnormal PKA activities.