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Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease.

ABSTRACT: AIMS:Neuroinflammation and redox dysfunction are recognized factors in Parkinson's disease (PD) pathogenesis, and diabetes is implicated as a potentially predisposing condition. Remarkably, upregulation of glutaredoxin-1 (Grx1) is implicated in regulation of inflammatory responses in various disease contexts, including diabetes. In this study, we investigated the potential impact of Grx1 upregulation in the central nervous system on dopaminergic (DA) viability. RESULTS:Increased GLRX copy number in PD patients was associated with earlier PD onset, and Grx1 levels correlated with levels of proinflammatory tumor necrosis factor-alpha (TNF-?) in mouse and human brain samples, prompting mechanistic in vitro studies. Grx1 content/activity in microglia was upregulated by lipopolysaccharide (LPS), or TNF-?, treatment. Adenoviral overexpression of Grx1, matching the extent of induction by LPS, increased microglial activation; Grx1 silencing diminished activation. Selective inhibitors/probes of nuclear factor ?B (NF-?B) activation revealed glrx1 induction to be mediated by the Nurr1/NF-?B axis. Upregulation of Grx1 in microglia corresponded to increased death of neuronal cells in coculture. With a mouse diabetes model of diet-induced insulin resistance, we found upregulation of Grx1 in brain was associated with DA loss (decreased tyrosine hydroxylase [TH]; diminished TH-positive striatal axonal terminals); these effects were not seen with Grx1-knockout mice. INNOVATION:Our results indicate that Grx1 upregulation promotes neuroinflammation and consequent neuronal cell death in vitro, and synergizes with proinflammatory insults to promote DA loss in vivo. Our findings also suggest a genetic link between elevated Grx1 and PD development. CONCLUSION:In vitro and in vivo data suggest Grx1 upregulation promotes neurotoxic neuroinflammation, potentially contributing to PD. Antioxid. Redox Signal. 25, 967-982.

SUBMITTER: Gorelenkova Miller O

PROVIDER: S-EPMC5175443 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease.

Gorelenkova Miller Olga O Behring Jessica Belle JB Siedlak Sandra L SL Jiang Sirui S Matsui Reiko R Bachschmid Markus M MM Zhu Xiongwei X Mieyal John J JJ

Antioxidants & redox signaling 20160627 18

<h4>Aims</h4>Neuroinflammation and redox dysfunction are recognized factors in Parkinson's disease (PD) pathogenesis, and diabetes is implicated as a potentially predisposing condition. Remarkably, upregulation of glutaredoxin-1 (Grx1) is implicated in regulation of inflammatory responses in various disease contexts, including diabetes. In this study, we investigated the potential impact of Grx1 upregulation in the central nervous system on dopaminergic (DA) viability.<h4>Results</h4>Increased G ...[more]

PMID: 27224303

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Project description:Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKC?) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKC? activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKC? contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including ?-synuclein, tumor necrosis factor ? (TNF?), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKC? with a concomitant increase in its kinase activity and nuclear translocation in both BV-2 microglial cells and primary microglia. Importantly, we also observed a marked upregulation of PKC? in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKC? in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKC? in primary microglia blunted the microglial proinflammatory response elicited by the inflammogens, including ROS generation, nitric oxide production, and proinflammatory cytokine and chemokine release. Importantly, we found that PKC? activated NF?B, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NF?B led to translocation of the p65 subunit to the nucleus, I?B? degradation and phosphorylation of p65 at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKC? attenuated NF?B activation, suggesting that PKC? regulates NF?B activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKC? in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKC? deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKC? knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKC? knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKC? in PD pathology, whereby sustained PKC? activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We conclude that inhibiting PKC? activation may represent a novel therapeutic strategy in PD treatment.

Project description:BACKGROUND:Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SN) while neighboring ventral tegmental area (VTA) DA neurons are relatively spared. Mechanisms underlying the selective protection of the VTA and susceptibility of the SN are still mostly unknown. Here, we demonstrate the importance of balance between astrocytes and microglia in the susceptibility of SN DA neurons to the PD mimetic toxin 1-methyl-4-phenylpyridinium (MPP+). METHODS:Previously established methods were used to isolate astrocytes and microglia from the cortex (CTX), SN, and VTA, as well as embryonic midbrain DA neurons from the SN and VTA. The transcriptional profile of isolated microglia was examined for 21 canonical pro- and anti-inflammatory cytokines by qRT-PCR with and without MPP+ exposure. Homo- and heterotypic co-cultures of neurons and astrocytes were established, and the effect of altering the ratio of astrocytes and microglia in vitro on the susceptibility of midbrain DA neurons to the PD mimetic toxin MPP+ was investigated. RESULTS:We found that regionally isolated microglia (SN, VTA, CTX) exhibit basal differences in their cytokine profiles and that activation of these microglia with MPP+ results in differential cytokine upregulation. The addition of microglia to cultures of SN neurons and astrocytes was not sufficient to cause neurodegeneration; however, when challenged with MPP+, all regionally isolated microglia resulted in exacerbation of MPP+ toxicity which was alleviated by inhibition of microglial activation. Furthermore, we demonstrated that isolated VTA, but not SN, astrocytes were able to mediate protection of both SN and VTA DA neurons even in the presence of exacerbatory microglia; however, this protection could be reversed by increasing the numbers of microglia present. CONCLUSION:These results suggest that the balance of astrocytes and microglia within the midbrain is a key factor underlying the selective vulnerability of SN DA neurons seen in PD pathogenesis and that VTA astrocytes mediate protection of DA neurons which can be countered by greater numbers of deleterious microglia.

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Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease.

Publications

Upregulation of Glutaredoxin-1 Activates Microglia and Promotes Neurodegeneration: Implications for Parkinson's Disease.

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