Study Rationale:
Gain-of-function mutations in LRRK2 cause familial Parkinson’s disease (PD) and increase the risk of developing the sporadic form of the disease. However, how hyperactive LRRK2 leads to PD remains unclear. Recent progress has shown that active LRRK2, via RAB substrates and their effector proteins, regulates key intracellular pathways including autophagosome retrograde transport, primary cilia formation/centriole cohesion and lysosomal tubule formation. Here, we aim to study these processes by surveying pathway interdependence, cell type specificity and molecular characterization of phospho-RAB effectors.
Hypothesis:
We hypothesize that one shared core mechanism involving phospho-RAB effector protein interactions may cause the apparently diverse cellular deficits mediated by pathogenic LRRK2.
Study Design:
Three critically important cellular pathways are affected by pathogenic LRRK2. This project will fill important knowledge gaps regarding the cell type specificity of the effect of hyperactive LRRK2 on these pathways, and the extent to which these alterations are interconnected. In addition, the project will provide important mechanistic insights into how phospho-RAB effectors affect each pathway.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Insights gained may enable specific rescue of the autophagosome transport, ciliogenesis/centriole cohesion, and lysosome dynamics defects in future more translational studies and help to uncover new potential targets for therapeutic intervention.
Next Steps for Development:
Cellular readouts may nominate potential biomarkers that are able to stratify patients with PD due to hyperactive LRRK2.