LRRK2 regulation of immune cell function and inflammatory response in G2019S BAC transgenic mice presented with environmental challenges
Mary K Herrick1, Darcie A Cook1, Jacob Kohlmeier2, Jeremy M Boss2, Malú G Tansey1 1Department of Physiology, 2Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta GA 30322
Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are known as the greatest contributor to dominantly inherited Parkinson's disease (PD) and are also associated with sporadic PD. LRRK2 G2019S, the most common autosomal dominantly inherited mutation, results in increased kinase activity; therefore, most therapeutic intervention has focused on the development of LRRK2 kinase inhibitors to dampen kinase activity. While most research has focused on the role of LRRK2 in neurons and neuronal toxicity, LRRK2 is highly expressed in immune cells, underlining the importance of understanding LRRK2's function in immune cells. Recent work from our group revealed immune cells from sporadic PD patients have increased LRRK2 levels compared to healthy controls, suggesting a role for a gene by environment interaction. Given that increased brain and peripheral inflammation have been associated with the pathophysiology of PD, aging is the number one risk factor for PD, and humans are exposed to a number of environmental challenges, we hypothesize that LRRK2 negatively regulates immune function in a synergistic gene by environment “double-hit” model. To directly investigate the role of LRRK2 in immune cells, we used BAC transgenic mice overexpressing WT or G2019S mLRRK2. Peripheral immune cells were immunophenotyped in aging mice to determine the effects of increased LRRK2 protein and/or increased LRRK2 kinase activity as a function of age. To assess a gene by environment synergistic effect, mice were exposed to three immune challenges (influenza, Listeria monocytogenes, and LCMV) +/- PF-360, a LRRK2 kinase inhibitor. Brain and peripheral immune cells were assessed by flow cytometry. Inflammatory genes were assessed by qPCR. Completion of these studies will provide valuable information into the role of LRRK2 in aging immune cells as well as the regulation of LRRK2 protein and its kinase activity in gene by environment models. In addition, they will examine the effects that LRRK2 kinase inhibitors will afford to immune system function in familial and sporadic PD.
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