Study Rationale: The LRRK2 gene is one of the most important genes involved in increasing the risk of Parkinson’s disease (PD). Changes in the gene, called mutations, can cause people to develop PD – although we still don’t fully understand what these mutations do. Some changes, which alter a regulatory region of the LRRK2 protein, may even confer protection from PD. Learning more about whether and how these protective variants might compensate for PD-linked mutations could lead to new avenues for effective therapeutics.
Hypothesis: We hypothesize that changes to the regulatory region of LRRK2 can compensate for mutations that are associated with PD.
Study Design: We will use immune cells, called macrophages, that have been genetically engineered to produce an altered version of LRRK2 to evaluate the effects of targeting the regulatory region that “switches” LRRK2 on and off. We will monitor the activity of LRRK2 in these cells by isolating proteins that LRRK2 tags with a chemical marker when it is active. We will compare the activity of the normal form of LRRK2 to the genetically engineered form, and then test whether the switch region can compensate for the impact of PD-associated mutations.
Impact on Diagnosis/Treatment of Parkinson’s disease: If our hypothesis is correct, then the switch portion of LRRK2 has the potential to be an additional target for the development of drugs to slow the progression of PD by modulating LRRK2.
Next Steps for Development: The next steps for this research will be to use our cellular model to assess how drugs designed to manipulate the LRRK2 regulatory switch alter LRRK2 activity.