Involvement of Interferon-γ in Microglial-Mediated Loss of Dopaminergic Neurons

Mount, Matthew; Lira, Arman; Grimes, David A.; Smith, Patrice D.; Faucher, Sylvie; Slack, Ruth S.; Anisman, Hymie; Hayley, Shawn; Park, David

doi:10.1523/jneurosci.5321-06.2007

Cited by 284 publications

(241 citation statements)

References 65 publications

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“…This cell loss was accompanied with compensatory sprouting and the appearance of dysmorphic and beading neurites, as well as microgliosis, a result congruent with the notion that microglia may induce neuritic beading during neuronal dysfunction (24). Furthermore, findings of compensatory sprouting upon cell loss, dysmorphic neurites, and an increase in proinflammatory responses are all present in postmortem samples from PD patients (25)(26)(27)(28)(29)(30). Therefore, given the early age of onset of degeneration in these mice, our findings are of particular significance and may correlate with features of autosomal recessive PD.…”

Section: Discussionsupporting

confidence: 72%

“…After being perfused transcardially, mouse brains were fixed in 4% paraformaldehyde and cryoprotected as described elsewhere (34). Midbrain sections containing the SNc (40 μm), pontine sections containing LC (40 μμ), and striatal (14 μm) sections were immunostained via avidin-biotin complex staining as described previously (26).…”

Section: Methodsmentioning

confidence: 99%

“…DA neuron survival in the SNc was blindly assessed by stereology using Stereo Investigator as described previously (26). Striatal TH quantification was performed at 200×.…”

Section: Methodsmentioning

confidence: 99%

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Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Rousseaux

Marcogliese

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1–nullizygous mice, when fully backcrossed to a C57BL/6J background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta , progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1–related degeneration in mice.

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Section: Discussionsupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

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Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Rousseaux

Marcogliese

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The cytokines chosen for assessment were interferon‐γ (IFNγ), tumour necrosis factor‐α (TNFα) and interleukin‐1β (IL‐1β) as these cytokines are linked to both MHC II induction (Dong and Benveniste, 2001) and PD pathogenesis (Mogi et al, 1994a, 1994b; Mount et al, 2007). Saline‐treated MHC II null mice had higher levels of IFNγ than saline‐treated wild‐type mice ( P = 0.040 ANOVA, Student Newman Keuls post hoc test; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Irrespective of their source, all these cytokines are increased in PD patients (Mogi et al, 1994a, 1994b; Mount et al, 2007) and are documented to have negative impacts on MPTP toxicity (Mount et al, 2007; Ferger et al, 2004). Indeed IFNγ null mice showed significant attenuation of MPTP‐induced loss of dopaminergic neurons together with ablation of microgliosis (Mount et al, 2007), suggesting that IFNγ activation of microglia is important in MPTP toxicity. TNF‐α null mice also showed attenuation of MPTP toxicity, but this effect was confined to the striatum (Ferger et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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Mapping and kinetics of microglia/neuron cell-to-cell contacts in the 6-OHDA murine model of Parkinson's disease

Virgone-Carlotta

Uhlrich

Akram

et al. 2013

Glia

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As neuroinflammatory processes are involved in the pathogenesis of Parkinson's disease (PD), we provide several key data describing the time-course of microglial accumulation in relation with behavioral alterations and neurodegeneration in a murine model of PD induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). Our study argues for a major role of microglia which accumulation is somehow early and transient in spite of the neuronal loss progression. Moreover, we observed less 6-OHDA-induced neurodegeneration associated with less inflammatory reaction in DAP-12 Knock-In mice. The direct cell-to-cell contacts that may support physical interactions between microglia and altered dopaminergic neurons are ill-defined, while it is currently hypothesized that microglia support an immune-mediated amplification of neurodegeneration by establishing a molecular cross talk with neurons. Indeed, we sought to map microglia/neuron appositions in substantia nigra (SN) of 6-OHDA injected C57Bl/6 mice and CX3CR1/(GFP/+) mice. Confocal immunofluorescence analyses followed by 3D reconstitutions reveal close appositions between the soma of TH+ neurons and microglial cell bodies and ramifications. Interestingly, some microglial ramifications penetrated TH(+) somas and about 40% of GFP(+) microglial cells in the injured SN harbored TH(+) intracytoplasmic inclusions. These results suggest a direct cross talk between neurons and microglia that may exert a microphagocytic activity toward TH+ neurons. Altogether, these results obtained in a murine PD model may participate in the understanding of microglial cells' function in neurodegenerative diseases.

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Involvement of Interferon-γ in Microglial-Mediated Loss of Dopaminergic Neurons

Abstract: Growing evidence implicates microglia in the loss of dopaminergic neurons in Parkinson's disease (PD).

Cited by 284 publications

References 65 publications

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Mapping and kinetics of microglia/neuron cell-to-cell contacts in the 6-OHDA murine model of Parkinson's disease

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