Convergence of LRRK2 and GBA in the Pathogenesis of Parkinson’s Disease Supplement

Promising Outcomes of Original Grant:
In our original project we used dopamine cells derived from induced pluripotent stem cells (iPSCs) from people with Parkinson’s-associated LRRK2 or GBA mutations. This work studied potential connections between the Parkinson’s-associated proteins LRRK2 and GCase, which is encoded by the GBA gene. We identified that GCase activity is significantly reduced in neurons with LRRK2 mutations. Additionally, we found that treatment with drugs to inhibit LRRK2 increased GCase activity not only in neurons with LRRK2 mutations, but also in neurons with GBA mutations. These results suggest that LRRK2 plays a role in regulation of GCase in neurons.

Objectives for Supplemental Investigation:          
The goal of this research is to improve our understanding of the role of LRRK2 in regulation of GCase activity. First, we will expand our analysis of neurons with LRRK2 mutations to increase our confidence in previous studies. We will then examine several possible mechanisms through which LRRK2 could be regulating GCase activity in a cell. This information will improve our understanding of the biology behind the observations made in our previously funded project.

Importance of This Research for the Development of a New Parkinson’s Therapy:   
Our work highlights a potential role of LRRK2 in the regulation of GCase activity. This is important as therapeutic development of drugs targeting either the inhibition of LRRK2 or activation of GCase are currently in clinical trials. Our results could provide insight into whether LRRK2 inhibitors could be effective in GBA mutation carriers or whether GCase-targeting therapies could be used in LRRK2 mutation carriers.