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

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, Cx3Cr1-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.

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…In addition, several other exogenous stimuli or environmental toxins have been found to be responsible for producing neuronal damage by disrupting mitochondrial and lysosomal function and by producing ROS and other proteinaceous insults in PD . Toxins that produce PD‐like effects in both cellular and animal models, such as 1‐methyl‐4‐phenylpyridinium (MPP + ), 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), 6‐hydroxydopamine (6‐OHDA), and paraquat, have been shown to activate the NLRP3 inflammasome in many recent studies …”

“…37 Toxins that produce PD-like effects in both cellular and animal models, such as 1-methyl-4-phenylpyridinium (MPP + ), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), and paraquat, have been shown to activate the NLRP3 inflammasome in many recent studies. [38][39][40][41] On sensing particular stimuli, NLR proteins process a set of sequential signals to form the inflammasome. 42 The expression of pro-IL-1β and pro-IL-18 is triggered by the transcription factor nuclear factor kappa light chain enhancer of activated B cells (NF-κB).…”

Submicron Crystals of the Parkinson’s Disease Substantia nigra: Calcium Oxalate, Titanium Dioxide and Iron Oxide

“…In mice, activation of microglial NLRP3 inflammasome by misfolded α-synuclein causes the death of proximal dopaminergic neurons. [1,3,[8][9][10][11] The found TiO2 particles are coated with a protein-layer, constituting about 20 % of their mass. TiO2, shown to adsorb and orient peptides and polymers [27][28][29] could also adsorb α-synuclein or its precursor peptides.…”

“…Studies of the past 5 years have shown that a cause of the degeneration is inflammatory attack of dopaminergic neurons of the substantia nigra by microglia when their NLRP3 inflammasome is activated by phagocytized misfolded α-synuclein. [1][2][3][4][5][6][7][8][9][10][11][12] The misfolded β-sheet-rich α-synuclein aggregates in PD's hallmark Lewy bodies. If misfolded α-synuclein templates the misfolding of more synuclein, it constitutes a PD-propagating prion.…”

Neurodegenerative Susceptibility During Maternal Nutritional Programing: Are Central and Peripheral Innate Immune Training Relevant?

“…Finally, the role of metabolic species regulating the NLRP3inflammasome and neurodegeneration was recently evidenced by showing that the 25-hydroxycholesterol also activates the NLRP3-inflammasome pathway, promoting progressive neurodegeneration in X-linked adrenoleukodystrophy, a nervous disease with cerebral inflammatory demyelination (Jang et al, 2016). Moreover, the NLRP3 inflammasome pathway has been identified to contribute to PD (Fan et al, 2017;Gordon et al, 2018;Lee et al, 2018), AD and ALS (Heneka et al, 2013;Johann et al, 2015), HD (Glinsky, 2008), as well as to behavioral alterations in mice at later stages, such as anhedonia (Zhu et al, 2017), anxiety (Lei et al, 2017) and depression-like behavior (Pan et al, 2014;Su et al, 2017).…”