Study Rationale:
Genetic studies for Parkinson's disease have indicated that variants of the LRRK2 gene are associated with increased risk of Parkinson's disease. However, we still know very little about the molecular mechanisms underlying these variants. Our preliminary data provides substantial evidence that LRRK2 genetic variants alter the expression of LRRK2 in immune cells in the blood (i.e., monocytes).
Hypothesis:
We hypothesize that there are multiple independent genetic variants at LRRK2 and that some of these control the expression of LRRK2 in immune cells (monocytes). We further hypothesize that LRRK2 variants associated with Parkinson's may have distinct effects on LRRK2 kinase activity in these immune cells.
Study Design:
We will use computational methods to identify causal variant(s) at LRRK2. We will then use gene expression data to understand the functional consequences of LRRK2 variants in immune cells. Finally, we will investigate the effect of Parkinson's-associated LRRK2 mutations and other variants on kinase activity in immune cells.
Impact on Diagnosis/Treatment of Parkinson's disease:
Better understanding the impact of LRRK2 causal variants in immune cells is expected to reveal ways in which altered LRRK2 function may contribute to the progression of Parkinson's. The results from this study may also help researchers design better clinical trials to test LRRK2 kinase inhibitors.
Next Steps for Development:
If this study is successful, we will proceed to set up an experimental validation scheme to test the impact of LRRK2 variants on cellular activity in immune cells. We will also increase the sample size to test the impact of different LRRK2 variants on kinase activity in immune cells.