Study Rationale: Although most cases of Parkinson’s disease (PD) are of unknown origin, some forms can be inherited. Mutations that activate the enzyme LRRK2 are a major cause of inherited PD, and LRRK2 is therefore an important target for drug development. Pathogenically activated LRRK2 chemically modifies a set of proteins called Rabs by a process called phosphorylation. We have discovered that inactivation of several other genes can alter the phosphorylation of the same Rab proteins. In this project, we will characterize six of these selected genes to understand how they modify or curtail LRRK2 action.
Hypothesis: Our hypothesis is that loss of these genes influences the ability of another enzyme, called a phosphatase, to remove phosphate groups from Rab proteins, reversing the activity of LRRK2.
Study Design: Our previous studies identifying these genes were conducted in cells called fibroblasts. Here, we propose to inactivate the six genes individually in isolated neurons to verify that loss of these genes influences LRRK2 action in brain cells. We will also monitor the effect of this genetic manipulation has on the location and function of the phosphatase PPM1H, and assess its ability to counteract LRRK2 action using biochemical and microscopic approaches.
Impact on Diagnosis/Treatment of Parkinson’s disease: These studies could point toward alternative pathways to target for development of drugs that will benefit people with PD in the future.
Next Steps for Development: These studies may enable us to design novel small molecules or gene-inactivating therapeutics to counteract hyperactive LRRK2.