Genetic studies in Parkinson's disease (PD) have led to the discovery of several causal and risk genes, whose mutations contribute to some forms of PD; among those described are mutations in LRRK2 and GBA1. Recent genetic studies have found that individuals with mutations in both GBA1 and LRRK2 exhibit PD symptoms much earlier than the average age at onset in individuals who carry LRRK2 or GBA1 mutation alone. Here, we plan to examine the mechanisms of GBA1-LRRK2 interaction using human dopaminergic neurons derived from individuals with PD generated using induced pluripotent stem cells ("man-made" stem cells that can become other cell types; iPSCs). This work aims to develop therapeutic strategies that target these converging pathogenic pathways in PD.
Recent genetic studies have found that individuals with mutations in both GBA1 and LRRK2 exhibit PD symptoms at an earlier age, suggesting a possible synergistic effect of the two variants in disease pathogenesis. We will explore the molecular nature of this clinical phenomena to identify converging therapeutic targets.
We plan to use pre-clinical LRRK2 models and human dopaminergic neurons derived from iPSCs to study the effect of LRRK2 mutations or LRRK2 kinase inhibitors on glucocerebrosidase (an enzyme made by the GBA gene).
Impact on Diagnosis/Treatment of Parkinson's disease:
Using this approach, we may uncover nodes of convergence between LRRK2 and GBA1 that will allow for development of novel therapeutics for PD patients who carry these mutations.
Next Steps for Development:
An interaction between LRRK2 and GBA1 could provide insights into the therapeutic efficacy of LRRK2 kinase inhibitors in the GBA population and GBA-targeted therapies in LRRK2 carriers.