Study Rationale:
Genes can influence one's chance of developing Parkinson's disease (PD), but it's not entirely clear how. In this study, we will use cells from people with Parkinson's to test how the LRRK2 gene causes the disease. This gene is important because it is involved in PD with genetic causes (inherited) as well as in the disease whose causes are unknown (sporadic). We aim to find out why.
Hypothesis:
We hypothesize that individual variations in the LRRK2 gene define how it responds to inflammation, making it overactive in some cases.
Study Design:
In this study, we will use induced pluripotent stem cells -- cells that can give rise to any types of cells in the human body -- from people with PD who have Parkinson's-associated changes in LRRK2. We will turn these cells into microglia, which play the role of resident immune cells in the brain. We will then determine whether the Parkinson's-associated changes in LRRK2 affect how the gene works. These studies will be conducted either under standard conditions or under conditions that re-create inflammation in the brain.
Impact on Diagnosis/Treatment of Parkinson's disease:
If we find that the LRRK2 gene in people with sporadic disease is overactive, as it is in people with inherited disease, then this may open up the possibility that sporadic PD can be treated with therapies designed for inherited PD.
Next Steps for Development:
If overactive LRRK2 is associated with a higher risk of Parkinson's, then we might consider this genetic risk factor in selecting clinical trial participants.