Published in:
01-12-2022 | Parkinson's Disease | Research
The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson’s disease via the microglial NLRP3 inflammasome
Authors:
Liang Kou, Xiaosa Chi, Yadi Sun, Chao Han, Fang Wan, Junjie Hu, Sijia Yin, Jiawei Wu, Yunna Li, Qiulu Zhou, Wenkai Zou, Nian Xiong, Jinsha Huang, Yun Xia, Tao Wang
Published in:
Journal of Neuroinflammation
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Issue 1/2022
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Abstract
Background
Circadian disturbance is a common nonmotor complaint in Parkinson’s disease (PD). The molecular basis underlying circadian rhythm in PD is poorly understood. Neuroinflammation has been identified as a key contributor to PD pathology. In this study, we explored the potential link between the core clock molecule Rev-erbα and the microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome in PD pathogenesis.
Methods
We first examined the diurnal Rev-erbα rhythms and diurnal changes in microglia-mediated inflammatory cytokines expression in the SN of MPTP-induced PD mice. Further, we used BV2 cell to investigate the impacts of Rev-erbα on NLRP3 inflammasome and microglial polarization induced by 1-methyl-4-phenylpyridinium (MPP+) and αsyn pre-formed fibril. The role of Rev-erbα in regulating microglial activation via NF-κB and NLRP3 inflammasome pathway was then explored. Effects of SR9009 against NLRP3 inflammasome activation, microgliosis and nigrostriatal dopaminergic degeneration in the SN and striatum of MPTP-induced PD mice were studied in detail.
Results
BV2 cell-based experiments revealed the role of Rev-erbα in regulating microglial activation and polarization through the NF-κB and NLRP3 inflammasome pathways. Circadian oscillation of the core clock gene Rev-erbα in the substantia nigra (SN) disappeared in MPTP-induced PD mice, as well as diurnal changes in microglial morphology. The expression of inflammatory cytokines in SN of the MPTP-induced mice were significantly elevated. Furthermore, dopaminergic neurons loss in the nigrostriatal system were partially reversed by SR9009, a selective Rev-erbα agonist. In addition, SR9009 effectively reduced the MPTP-induced glial activation, microglial polarization and NLRP3 inflammasome activation in the nigrostriatal system.
Conclusions
These observations suggest that the circadian clock protein Rev-erbα plays an essential role in attenuating neuroinflammation in PD pathology, and provides a potential therapeutic target for PD treatment.