Objective: To investigate the impact of PARK2, PINK1, and LRRK2 deficiency on neuroinflammation in aging, using immune-mediated mouse models.
Background: Emerging evidence links mitophagy-related genes, including PARK2 (PARKIN), PINK1, and LRRK2, to immune dysregulation in Parkinson’s disease (PD) and other neurodegenerative disorders. However, their role in age-related neuroinflammation remains unclear.
Method: We evaluated the effects of PARK2, PINK1, and LRRK2 deficiency in neuroinflammation using two models: myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) to assess immune-driven neurodegeneration, and lipopolysaccharide (LPS) administration to evaluate systemic inflammatory responses.
Results: PARK2 and PINK1 knockout mice (middle-aged and aged) developed more severe EAE, with incomplete recovery, increased monocyte, dendritic cell, and CD8⁺ T-cell responses, along with microglial activation and CNS immune infiltration. LRRK2 knockout mice were completely resistant to EAE, showing impaired thymic selection, homeostatic proliferation, regulatory T cell function, and dendritic cell maturation. LPS administration led to macrophage and plasma cell infiltration in the intestine, along with increased mitotic activity of crypt epithelial cells and epithelial dysplasia in knockout mice.
Conclusion: These findings highlight distinct roles of mitophagy-related genes in neuroinflammation. LRRK2-associated pathways may play a crucial role in modulating immune responses, with potential implications for PD pathogenesis and therapeutic targeting.
References: Cossu D, Hatano T, Hattori N. The Role of Immune Dysfunction in Parkinson’s Disease Development. Int J Mol Sci. 2023 Nov 26;24(23):16766. doi: 10.3390/ijms242316766.
Cossu D, Yokoyama K, Sato S, Noda S, Sakanishi T, Sechi LA, Hattori N. Age related immune modulation of experimental autoimmune encephalomyelitis in PINK1 knockout mice. Front Immunol. 2022 Nov 17;13:1036680. doi: 10.3389/fimmu.2022.1036680.
Cossu D, Yokoyama K, Sato S, Noda S, Sechi LA, Hattori N. PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE). J Neuroimmunol. 2021 Oct 15;359:577694. doi: 10.1016/j.jneuroim.2021.577694.
To cite this abstract in AMA style:
D. Cossu, H. Okada, S. Noda, Y. Tomizawa, S. Ueno, L. Sechi, T. Hatano, N. Hattori. Distinct roles of PARK2, PINK1, and LRRK2 in neuroinflammation: resistance and susceptibility in immune-mediated mouse models [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/distinct-roles-of-park2-pink1-and-lrrk2-in-neuroinflammation-resistance-and-susceptibility-in-immune-mediated-mouse-models/. Accessed November 20, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/distinct-roles-of-park2-pink1-and-lrrk2-in-neuroinflammation-resistance-and-susceptibility-in-immune-mediated-mouse-models/