Objective: In this study, we sought to determine if there is a synergistic effect of non-neurotropic H1N1 influenza and the G2019S LRRK2 mutation associated Parkinson’s disease (PD).
Background: PD is characterized by progressive loss of the DA neurons in the SNpc and DA in the Striatum. In addition, PD patients demonstrate a dysregulation in the immune system. The exact etiology of PD has long been debated, and current theories posit a role for gene x environment interactions. One of the most common PD mutations occur in the LRRK2 gene and accounts for 15% of familial and sporadic cases, suggesting that the same signaling pathways might be altered in sporadic PD by pathogenic environmental factors. LRRK2 is primarily expressed in peripheral immune cells, lungs, and the brain. The G2019S mutation enhances LRRK2’s endogenous kinase activity, which has a multitude of downstream effects including an overactive immune system. However, LRRK2’s low penetrance implies the need for an extra trigger to induce its pathogenicity. Given that viral infections, notably non-neurotropic Influenza, have historically sparked PD-like symptoms, we hypothesize that mutant LRRK2’s mode of action may be in the abnormalities in peripheral anti-viral response and inflammatory pathways.
Method: Using flow cytometry, immunohistochemistry, and multiplex immunoassays, we analyzed DA cell loss, central and peripheral immune responses in WT and G2019S LRRK2 mice following the infection with pandemic H1N1 Influenza (strain A/CA/04/2009).
Results: We found that H1N1-infected G2019S LRRK2 mice developed: higher mortality rate and viral load in the lungs compared to WT mice; 20% DA cell loss at 7-30 days post-infection; and elevated neuroinflammation that wasn’t resolved by 30 days post-infection. We next used cre/flox technology to selectively knock-out mutant LRRK2 in innate immune cell sub-sets selectively and found that a reduction of LRRK2 kinase activity in Cx3Cr1+ peripheral monocytes during viral infection rescues the neuronal loss in the SNpc.
Conclusion: The lack of direct viral brain infection highlights the importance of peripheral signals in triggering neuronal loss. The ongoing studies in the lab seek to understand the mechanisms of how mutant LRRK2 influences immune responses secondary to viral infection in experimental PD.
To cite this abstract in AMA style:
K. Crowther, R. Smeyne, E. Kozina. Dysregulated Anti-Viral Response in LRRK2 Mice Following Infection with H1N1 Influenza Induces DA Neuron Loss in the SNpc. [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/dysregulated-anti-viral-response-in-lrrk2-mice-following-infection-with-h1n1-influenza-induces-da-neuron-loss-in-the-snpc/. Accessed October 15, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/dysregulated-anti-viral-response-in-lrrk2-mice-following-infection-with-h1n1-influenza-induces-da-neuron-loss-in-the-snpc/