Mutations in the LRRK2 gene are a genetic cause of Parkinson’s disease (PD). However, the disease risk for carriers of LRRK2 mutations varies widely. Other genes — or genetic variations within LRRK2 itself — may modify the effect of LRRK2 mutation. In this study, we aim to replicate and validate our discovery of genes and genetic variants that modify the frequency and age of onset of PD with a LRRK2 mutation.
Our studies aim to explore the biological importance and therapeutic potential of a novel genetic modifier for LRRK2-associated PD. Such modifiers may allow us to regulate the activity of LRRK2 and its associated pathways.
Our goal is to replicate our initial genetic findings in participants with the most common type of LRRK2 mutation (p.G2019S) — both people with and without PD — as well as a group of control volunteers. We will then introduce these candidate modifiers into neurons that harbor the LRRK2 p.G2019S mutant gene to determine how they influence disease onset and progression. Our current experiments are focused on exploring how variants in the CORO1C gene influence the activity of cellular pathways associated with mutant LRRK2 in neurons.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Completion of this project will validate one or more modifiers that affect the onset or progression of LRRK2 PD. Our results will provide mechanistic insights and new targets for the development of therapeutics that can slow or halt disease progression.
Next Steps for Development:
Results from this study may help identify individuals who will respond positively in ongoing clinical trials of LRKK2 inhibitors. And, by further characterizing how these genetic modifiers influence LRRK2 function in pre-clinical models, we will advance the discovery of new therapeutics for PD.