LRRK2 G2019S promotes astrocytic inflammation induced by oligomeric α-synuclein through NF-κB pathway

Kai-Jie He; Jin-Bao Zhang; Jun-Yi Liu; Feng-Lun Zhao; Xiao-Yu Yao; Yu-Ting Tang; Jin-Ru Zhang; Xiao-Yu Cheng; Li-Fang Hu; Fen Wang; Chun-Feng Liu

doi:10.1016/j.isci.2023.108130

LRRK2 G2019S promotes astrocytic inflammation induced by oligomeric α-synuclein through NF-κB pathway

iScience. 2023 Oct 5;26(11):108130. doi: 10.1016/j.isci.2023.108130. eCollection 2023 Nov 17.

Authors

Kai-Jie He^{1

2}, Jin-Bao Zhang^{1

2}, Jun-Yi Liu³, Feng-Lun Zhao², Xiao-Yu Yao¹, Yu-Ting Tang², Jin-Ru Zhang¹, Xiao-Yu Cheng¹, Li-Fang Hu², Fen Wang^{1

2}, Chun-Feng Liu^{1

2

4}

Affiliations

¹ Department of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
² Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China.
³ Department of Neurology, Dushu Lake Hospital Affilicated to Soochow University, Suzhou, Jiangsu 215123, China.
⁴ Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830063, China.

Abstract

Parkinson's disease (PD) is characterized by the irreversible loss of dopaminergic neurons and the accumulation of α-synuclein in Lewy bodies. The oligomeric α-synuclein (O-αS) is the most toxic form of α-synuclein species, and it has been reported to be a robust inflammatory mediator. Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are also genetically linked to PD and neuroinflammation. However, how O-αS and LRRK2 interact in glial cells remains unclear. Here, we reported that LRRK2 G2019S mutation, which is one of the most frequent causes of familial PD, enhanced the effects of O-αS on astrocytes both in vivo and in vitro. Meanwhile, inhibition of LRRK2 kinase activity could relieve the inflammatory effects of both LRRK2 G2019S and O-αS. We also demonstrated that nuclear factor κB (NF-κB) pathway might be involved in the neuroinflammatory responses. These findings revealed that inhibition of LRRK2 kinase activity may be a viable strategy for suppressing neuroinflammation in PD.

Keywords: Biological sciences; Immunology; Molecular biology; Neuroscience.