The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson's disease via the microglial NLRP3 inflammasome

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.