MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration

Eunju Lee,Sangjun Park,Sujeong Hong,Boreum Hwang,Junghyun Son,Inhwa Hwang,Je-Wook Yu,Yoeseph Cho

doi:10.1038/s41418-018-0124-5

Abstract

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-1β 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, Cx3Cr1CreER-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.

Highlights

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by a progressiveEdited by D
The loss of dopaminergic neurons in the substantia nigra (SN) was significantly inhibited by the genetic ablation of caspase-1 or by treatment with a selective caspase-1 inhibitor in an animal PD model following the administration of MPTP or 6-hydroxydopamine administration [20, 45]
Yan et al demonstrated that dopaminergic neuronal loss was attenuated by NLRP3 deficiency in the MPTP-treated mouse model [38]

Summary

Introduction

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by a progressiveEdited by D. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by a progressive. In addition to the potential role of α-synuclein in PD pathogenesis, neuroinflammation has been implicated in the loss of dopaminergic neurons [6, 7]. To this end, increased pro-inflammatory cytokine levels have been found in striatal dopaminergic regions or cerebrospinal fluid of PD patients [8, 9], and in the SN in an animal model of PD [10]. Activated microglia might contribute to neuronal damage via the release of pro-inflammatory cytokines and neurotoxic products [11].

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Results

Conclusion