Approximately, 50,000 new cases of PD are diagnosed every year. With no current disease-modifying therapy available for PD patients, novel approaches that could be generated from these studies would have tremendous impact on PD patient care. Mutations in the lrrk2 gene give rise to the most common form of dominantly-inherited parkinsonism and are associated with an estimated 1-2% of total PD cases with an incidence of 40% in the Ashkenazi Jewish PD population. LRRK2 is abundantly expressed in cells of the immune system, including CD4+ and CD8+ T cells, CD14+ monocytes, and CD19+ B cells [2];yet its function in the immune system and the relationship of LRRK2 function in immune cells to PD pathogenesis is largely unknown. T cells, the major controllers and effectors of adaptive immunity are comprised of numerous subsets. When activated, each subset expresses specific effector functions. The composite of surface markers that define a T-cell subset and the specific effector functions associated with that subset delineate an immunophenotype that can define current and predict future immune responses. Here, we hypothesize that pathogenic LRRK2 mutations a) disrupt T-cell homeostasis and/or the ability of certain subsets to respond to activation signals and b) alter monocyte homeostasis and responses to activation. In support of our hypothesis, a recent report suggests that wild-type LRRK2 enhances Wnt signaling, a process that is important for T-cell differentiation and maintenance of CD8+ memory T cell pool. Therefore, we expect to find alterations in the balance of T-cell subsets and/or T-cell/monocyte dysfunction. Such alterations could lead to destruction of neurological tissue, including the midbrain dopaminergic neurons that degenerate in PD. To test our hypothesis, we propose to immunophenotype LRRK2 mutation carriers and non-carriers with or without PD. To accomplish this, we have established collaborations with five movement disorder clinics in Florida that have large numbers of potential LRRK2 mutation carriers. We will enroll and genotype LRRK2 in PD and healthy subjects and collect blood from these subjects. Using a set of standardized immunophenotyping markers developed for the Human Immunology Project, we will analyze by multi-color flow cytometry the frequencies of CD8 and CD4 T-cell subsets, which will include central and effector memory populations, as well as Th1, Th2, Th17, and Treg populations. We will also determine the levels of LRRK2 expression in immune cell subsets and their functional coupling to NFAT and Wnt signaling cascades. Lastly, we will compare the activation responses of T cells and monocytes to determine if LRRK2 affects this process. Completion of the above aims will provide the first view of immune effector cell differences between mutant LRRK2 carriers and controls and describe a role for LRRK2 in basic T-cell and monocyte responses and function. This dataset may reveal new and useful biomarkers of PD risk or disease severity and could lead to a novel immune-based therapy for PD patients carrying LRRK2 pathogenic alleles.

Public Health Relevance

The proposed research addresses a novel and paradigm-shifting mechanism-based hypothesis on the role of the adaptive immune system in the pathogenesis of sporadic late-onset Parkinson's Disease (PD). We propose that LRRK2 plays an important role in immune system responses and thus LRRK2 mutation carriers are at increased risk for development of PD due to immune dysregulation. The proposed hypothesis has the potential to have an extremely high impact on clinical care because it may pave the way for novel immunomodulatory approaches to diagnose, treat, or prevent PD onset.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS084647-01A1
Application #
8728473
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Sieber, Beth-Anne
Project Start
2014-02-15
Project End
2015-12-31
Budget Start
2014-02-15
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$234,000
Indirect Cost
$84,000
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322