Lee, Eunju Hwang, Inhwa Park, Sangjun Hong, Sujeong Hwang, Boreum Cho, Yoeseph Son, Junghyun Yu, Je-Wook 2024-01-19T21:01:27Z 2024-01-19T21:01:27Z 2021-09-02 2019-02 1350-9047 https://pubs.kist.re.kr/handle/201004/120428 Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the reduction of dopamine levels in the striatum. Although details of the molecular mechanisms underlying dopaminergic neuronal death in PD remain unclear, neuroinflammation is also considered a potent mediator in the pathogenesis and progression of PD. In the present study, we present evidences that microglial NLRP3 inflammasome activation is critical for dopaminergic neuronal loss and the subsequent motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Specifically, NLRP3 deficiency significantly reduces motor dysfunctions and dopaminergic neurodegeneration of MPTP-treated mice. Furthermore, NLRP3 deficiency abolishes MPTP-induced microglial recruitment, interleukin-1 beta production and caspase-1 activation in the SN of mouse brain. In primary microglia and mixed glial cell cultures, MPTP/ATP treatment promotes the robust assembly and activation of the NLRP3 inflammasome via producing mitochondrial reactive oxygen species. Consistently, 1-methyl-4-phenyl-pyridinium (MPP+) induces NLRP3 inflammasome activation in the presence of ATP or nigericin treatment in mouse bone-marrow-derived macrophages. These findings reveal a novel priming role of neurotoxin MPTP or MPP+ for NLRP3 activation. Subsequently, NLRP3 inflammasome-active microglia induces profound neuronal death in a microglia-neuron co-culture model. Furthermore, Cx3Cr1(CreER)-based microglia-specific expression of an active NLRP3 mutant greatly exacerbates motor deficits and dopaminergic neuronal loss of MPTP-treated mice. Taken together, our results indicate that microglial NLRP3 inflammasome activation plays a pivotal role in the MPTP-induced neurodegeneration in PD. English NATURE PUBLISHING GROUP PARKINSONS-DISEASE SUBSTANTIA-NIGRA ALZHEIMERS-DISEASE CIAS1 MUTATIONS ALPHA-SYNUCLEIN MOUSE MODEL CELL-DEATH 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE CONTRIBUTES MITOCHONDRIA MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration Article 10.1038/s41418-018-0124-5 1 CELL DEATH AND DIFFERENTIATION, v.26, no.2, pp.213 - 228 CELL DEATH AND DIFFERENTIATION 26 2 213 228 scie scopus 000455715000002 2-s2.0-85047224697 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article PARKINSONS-DISEASE SUBSTANTIA-NIGRA ALZHEIMERS-DISEASE CIAS1 MUTATIONS ALPHA-SYNUCLEIN MOUSE MODEL CELL-DEATH 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE CONTRIBUTES MITOCHONDRIA