Clinical Evaluation of LRRK2 Inhibitors on Inflammatory Responses in Crohn's and Parkinson's Diseases

Objective/Rationale:             
Leucine-rich repeat kinase 2 (LRRK2) is genetically associated with several human diseases, including Parkinson’s disease (PD) and Crohn’s disease (CD). Recent studies suggest that LRRK2 is involved in suppression of inflammation. We hypothesize that LRRK2 mutations found in PD and CD alter immune regulation. We will test how LRRK2 modifies inflammatory cytokine signaling in peripheral blood cells isolated from CD patients and from PD patients with the LRRK2 gene mutations, and how LRRK2 inhibitors modulate peripheral inflammation in vitro.  

Project Description:             
The first goal of the project is to determine whether LRRK2 regulates inflammatory cytokine signaling in peripheral blood cells sampled from CD patients. De-identified blood samples will be collected from control and CD patients, and the effect of the CD-linked LRRK2 mutation on inflammatory cytokine signaling will be studied. Specifically, we will look at type II interferon cytokine signaling, which is important because; second, we will determine whether type II interferon signaling is regulated by LRRK2 kinase activity in peripheral blood cells sampled from PD patients with LRRK2 mutations. We will also test how inhibitors of LRRK2 and NFAT (a potential target of LRRK2) modulate the type II interferon response in vitro. The study will be conducted in collaboration with Boston University and Mayo Clinic Florida.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
This project will elucidate the novel regulation mechanism of peripheral inflammation by LRRK2, which may be altered in specific genetic mutations of the gene as found in CD and familial PD patients.  Thus, our experiments will reveal whether inflammation in CD and PD could be ameliorated by targeting LRRK2 activity or its signaling cascade molecules.

Anticipated Outcome:          
The proposed work will tell us whether there is a difference in the induction of LRRK2 expression by type II interferon signaling in control versus CD or PD patients. If LRRK2 expression is reduced in CP or PD patients, we expect that this would enhance NFAT activity, thus enhancing the inflammatory response and disease etiology. In that case, LRRK2 kinase and NFAT inhibitors could be used therapeutically to suppress inflammation in CD and PD.