1. Down-regulation of DJ-1 Augments Neuroinflammation via Nrf2/Trx1/NLRP3 Axis in MPTP-induced Parkinson’s Disease Mouse Model
- Author
-
Hui-Lin Wang, Ya-Jie Ji, Xiang-Yang Ren, and Bian-Li Yin
- Subjects
0301 basic medicine ,NF-E2-Related Factor 2 ,Down-Regulation ,Small hairpin RNA ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Annexin ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,Neuroinflammation ,Gene knockdown ,Tyrosine hydroxylase ,Chemistry ,General Neuroscience ,MPTP ,Parkinson Disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Apoptosis ,Cancer research ,Microglia ,030217 neurology & neurosurgery - Abstract
Microglia-mediated neuroinflammation plays a significant role in the pathogenesis of Parkinson's disease (PD). Down-regulation of DJ-1, a PD-associated protein, has been recently found to increase microglial sensitivity to lipopolysaccharides (LPS). However, the role of DJ-1 in microglia-mediated neuroinflammation in PD remains unclear. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish a PD model with mice and tyrosine hydroxylase (TH) staining was performed to validate the model. Adenovirus strategy and shRNA was employed to knockdown the expression of DJ-1 in mice and BV2 microglia, respectively. Western Blot and quantitative PCR were carried out to determine the expression of cytokines, DJ-1, Nrf2, Trx1 and NRLP3. Immunoprecipitation was used to examine the potential interaction between DJ-1 and Nrf2 or Trx1. Flow cytometry-based Annexin V/7-AAD assay were performed to evaluate cell apoptosis. We found that down-regulation of DJ-1 exacerbated neuroinflammation in PD mice. DJ-1 and Nrf2 knockdown promoted inflammation and cell apoptosis in BV2 microglia, while NLRP3 knockdown had opposite effects. Furthermore, DJ-1 regulated the expression of NLRP3 by upregulating Nrf2/Trx1 axis. Taken together, these data suggested that down-regulation of DJ-1 accelerated microglia-mediated neuroinflammation and cell apoptosis via Nrf2/Trx1/NLRP3 axis. Thus, our results demonstrated the important role of DJ-1 in PD pathogenesis and warranted further investigation of DJ-1 as a therapeutic target for PD.
- Published
- 2020
- Full Text
- View/download PDF