Objective: Analyzing the mechanism of inflammatory response induced by oligomeric α-synuclein (O-αS) in LRRK2 G2019S mutation astrocytes to provide new targets and ideas for the treatment of PD.
Background: Neuroinflammation is implicated in the progression of Parkinson’s disease (PD). Leucine-rich repeat kinase 2 (LRRK2) is a potential therapeutic target for PD and may play a role in the regulation of inflammatory pathways. However, the underlying mechanism remains unclear. The present study investigated the mechanism of the astrocytic inflammatory response in LRRK2 G2019S mutation induced by oligomeric α-synuclein (O-αS).
Method: We established an O-αS induced inflammation model in LRRK2 G2019S mutant. Immunofluorescence or immunohistochemical staining was used for detecting activation and morphological changes of glial cells in mouse striatum, followed by morphological and fluorescence intensity analyses. The inflammatory levels of primary astrocytes with different treatments were detected by quantitative and semi-quantitative experimental approaches.
Results: Astrocytes are pivotal mediators of α-syn toxicity since they internalize and store α-syn released from damaged neurons. We found that LRRK2 G2019S enhanced the activation of astrocytes treated by O-αS in vivo. Morphological analysis showed that the astrocyte morphology of LRRK2 G2019S changed greatly, and the cell bodies were swollen and branched. LRRK2 G2019S also mediated dopaminergic neuronal loss in the O-αS induced mouse model. In vitro, LRRK2 G2019S aggravated astrocytic inflammation induced by O-αS through the nuclear factor-κB pathway, and inhibition of LRRK2 kinase activity reduced production of inflammatory factors.
Conclusion: LRRK2 G2019S is an important contributing factor leading to astrocytic inflammation, and inhibition of LRRK2 kinase activity is a viable strategy for suppressing neuroinflammation in the pathogenesis of PD.
To cite this abstract in AMA style:
JY. Liu, KJ. He, JB. Zhang, F. Wang, CF. Liu. LRRK2 G2019S promotes astrocytic inflammatory response induced by oligomeric α-synuclein through NF-κB pathway [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/lrrk2-g2019s-promotes-astrocytic-inflammatory-response-induced-by-oligomeric-%ce%b1-synuclein-through-nf-%ce%bab-pathway/. Accessed June 15, 2025.« Back to 2023 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-g2019s-promotes-astrocytic-inflammatory-response-induced-by-oligomeric-%ce%b1-synuclein-through-nf-%ce%bab-pathway/