Recent research suggests an about 30 percent higher rate of Parkinson's disease (PD) in people with Crohn's disease (CD) than in those without CD. This could be, at least in part, because LRRK2 mutations -- changes in the gene that controls the production of protein LRRK2 -- have been linked to both diseases. The frontline treatment for Crohn's disease was found to reduce Parkinson's risk by 78 percent. In this study, we aim to investigate the impact of LRRK2 mutations associated with both CD and PD on the LRRK2 protein and its interactions with other proteins, such as Rabs, in the blood and small intestine of people with Crohn's disease.
We hypothesize that two mutations that increase the risk of CD and PD, N2018D and G2019S, will activate LRRK2 in the blood and small intestine of people with CD. In contrast, we predict that another LRRK2 mutation, R1398H, which reduces the risk of both CD and PD, will lower LRRK2 activity.
To study how CD- and PD-associated mutations impact LRRK2, we will first evaluate the activity of regular LRRK2 and LRRK2 containing mutations in a robust cellular model. Next, we will evaluate LRRK2 activity in blood cells called monocytes and neutrophils and then in small intestine tissue donated by people with CD via biopsy. We will compare at least ten people with each mutation with people without LRRK2 mutations to ensure that our findings are true.
Impact on Diagnosis/Treatment of Parkinson's disease:
If our work reveals that mutations promoting Crohn's disease and Parkinson's disease activate LRRK2, it would mean that LRRK2 inhibitors currently being evaluated in clinical trials as potential treatments for PD might also be used for the treatment of Crohn's. This could help accelerate the approval of these compounds for the treatment of both diseases.
Next Steps for Development:
In the future, it would be important to better understand how the therapy for Crohn's disease that reduces the risk of PD influences LRRK2 activity. Specifically, we will need to determine whether inflammation that causes CD activates LRRK2 and/or whether increased LRRK2 activity caused by mutations and other factors promotes inflammation that leads to CD.