Study Rationale:
There is contradictory evidence on whether the LRRK2 and GBA genes, and the proteins that they encode, interact in their effects on Parkinson’s disease. Some studies suggest that LRRK2 variants increase activity of the enzyme encoded by GBA: glucocerebrosidase (GCase). Other studies show the opposite: that LRRK2 variants decrease GCase activity.
Hypothesis:
We hypothesize that different genetic variants in LRRK2 have differential effects on GCase activity, in different cell types that are relevant in Parkinson’s disease.
Study Design:
We will use cellular models to study the interaction between LRRK2 variants and GCase activity. Particularly, we will generate specific types of brain cells (dopamine and microglial cells) considered to be highly relevant in Parkinson’s disease research from induced pluripotent stem cells from people with PD who have specific LRRK2 variants. We will then perform different experiments in these cell models, to examine how the genetic variants in LRRK2 affect GCase activity and other measures in the cells.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our study will increase our understanding of the biological mechanisms that lead to Parkinson’s disease. In addition, it has the potential to affect future treatment. For example, if indeed variants in LRRK2 are reducing GCase activity, it is possible that treatments to increase GCase activity may benefit patients who have LRRK2 genetic variants. Conversely, if we find that LRRK2 variants increase GCase activity of glucocerebrosidase, it will mean that those patients will likely not benefit from GCase activators.
Next Steps for Development:
Both LRRK2 and GBA are targets for novel treatment approaches. The results of this study will help us better understand how these two genes interact and what drug targets will be relevant to patients with genetic variants in these genes. This study will also lead to future studies aiming to understand the mechanisms underlying Parkinson’s disease.