Objective/Rationale:
Mutations in LRRK2 are the most common cause of genetic PD. LRRK2 has also been recently linked to inflammatory bowel diseases (IBD), such as Crohn’s and ulcerative colitis. Data now suggest that LRRK2 is an important modulator in the immune system. Thus, it is important to determine if immune system alterations may play a role in LRRK2-PD and if overlap in pathogenic pathways may increase our understanding of PD, offering new therapeutic targets.
Project Description:
We will utilize newly created LRRK2 BAC-transgenic pre-clinical models expressing disease-causing mutations. The overall goal is to: determine if newly created transgenic models exhibit functional alterations in the immune system that elucidate overlap in pathogenic mechanisms between IBD and PD. We will test the hypothesis that BAC-transgenic models expressing PD-causing LRRK2 mutations will exhibit immunological dysfunction and a heightened inflammatory response after toxicant administration. Our experiments aim to answer three straightforward questions in this proposal: (i) do models expressing PD-causing human mutations exhibit immune system dysfunction (ii) does mutated LRRK2 expression confer differences in the immune system response after a PD-relevant inflammatory insult (LPS) and (iii) can these new LRRK2 models identify mechanistic overlaps between IBD and PD?
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The completion of these experiments are expected to: (i) provide a new pre-clinical model for investigating the role immune system dysfunction in PD (ii) determine if LRRK2 models respond differently to a PD-relevant inflammatory insult (iii) identify mechanistic links between immunological dysfunction in IBD disease and PD and (iv) identify immunological pathways that may be therapeutic targets in LRRK2 patients.
Anticipated Outcome:
We expect that pre-clinical models expressing mutated LRRK2 will exhibit alterations in immunological function and response to PD-relevant inflammatory insults. We anticipate that the identification of overlap of pathogenic mechanisms between IBD and PD will help us to better understand how mutations in LRRK2 elicit PD and, potentially identify new pathways as therapeutic targets.