Convergence of LRRK2 and GBA1 in the pathogenesis of Parkinson' Disease

Project: Research project

Description

In our original proposal we used human dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) with PD-associated LRRK2 or GBA1 mutations to study potential connections between the Parkinson’s disease associated proteins LRRK2 and glucocerebrosidase (GCase), which is encoded by the gene GBA1. We identified that GCase activity is significantly reduced in neurons with PD associated-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 GBA1 (encodes for GCase) mutations. These results suggest that LRRK2 plays a role in regulation of GCase in neurons.
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, which showed that neurons with LRRK2 mutations have reduced GCase activity that could be contributing to disease. 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 previous grant.
StatusActive
Effective start/end date6/10/196/9/21

Funding

  • Michael J. Fox Foundation for Parkinson's Research (16841)

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Glucosylceramidase
Parkinson Disease
Neurons
Mutation
Induced Pluripotent Stem Cells
Organized Financing
Dopaminergic Neurons