MHCII Is Required for  -Synuclein-Induced Activation of Microglia, CD4 T Cell Proliferation, and Dopaminergic Neurodegeneration

Harms, Ashley S.; Cao, Shuwen; Rowse, Amber L.; Thome, Aaron D.; Li, Xinru; Mangieri, Leandra R.; Cron, Randy Q.; Shacka, John J.; Raman, Chander; Standaert, David G.

doi:10.1523/jneurosci.5610-12.2013

Cited by 326 publications

(329 citation statements)

References 39 publications

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“…Microglial activation has been previously described in rAAV2-α-synuclein-transduced rodents (12,14,17). In WT rats transduced with α-synuclein, we observed a significant recruitment of CD68-positive cells within the SNpc (Fig.…”

Section: Resultssupporting

confidence: 74%

“…The LPS receptor TLR4 is poorly or not expressed in neurons and requires the function of innate immune cells including microglia and macrophages to elicit neurodegeneration. α-synuclein-related toxicities in the midbrain also appear to require innate immune cell action, as MHC-II knockout mice are protected from dopaminergic neurodegeneration (14). We therefore hypothesized that LRRK2 pathobiological function may not be fully appreciated without significant neuroinflammatory mechanisms driving aspects of neuronal dysfunction and degeneration in model systems.…”

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confidence: 99%

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Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Daher

Volpicelli‐Daley

Blackburn

et al. 2014

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

198

208

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Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disorders. These discrepancies may be caused by uncertainty in the pathobiological mechanisms of LRRK2 action. Previously, we found that LRRK2 knockdown inhibited proinflammatory responses from cultured microglia cells. Here, we report LRRK2 knockout rats as resistant to dopaminergic neurodegeneration elicited by intracranial administration of LPS. Such resistance to dopaminergic neurodegeneration correlated with reduced proinflammatory myeloid cells recruited in the brain. Additionally, adeno-associated virus-mediated transduction of human α-synuclein also resulted in dopaminergic neurodegeneration in wild-type rats. In contrast, LRRK2 knockout animals had no significant loss of neurons and had reduced numbers of activated myeloid cells in the substantia nigra. Although LRRK2 expression in the wild-type rat midbrain remained undetected under nonpathological conditions, LRRK2 became highly expressed in inducible nitric oxide synthase (iNOS)-positive myeloid cells in the substantia nigra in response to α-synuclein overexpression or LPS exposures. Our data suggest that knocking down LRRK2 may protect from overt cell loss by inhibiting the recruitment of chronically activated proinflammatory myeloid cells. These results may provide value in the translation of LRRK2-targeting therapeutics to conditions where neuroinflammation may underlie aspects of neuronal dysfunction and degeneration.M issense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can be found in many families that transmit classical late-onset Parkinson disease (PD) from one generation to the next. Notably, these mutations are prevalent in the Ashkenazi Jewish and North African Arab Berber populations in more than 20% of PD cases (1, 2). Genome-wide association studies further provide evidence that links LRRK2 to PD susceptibility, with several risk alleles being identified in LRRK2 (3, 4). Association studies have also linked LRRK2 to Crohn disease and Hansen disease (5, 6). Although LRRK2 is widely considered an exciting target for therapeutic approaches in PD, the pathobiological role of LRRK2 as a critical modifier of disease susceptibility is not well understood. Additional insights into LRRK2-linked molecular pathways relevant to PD and neurodegeneration may enable more predictive preclinical studies.PD is pathologically characterized by both α-synuclein inclusions called Lewy bodies and Lewy neurites and the profound loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The absence of LRRK2 has been shown to impair α-synuclein inclusion formation, neuron loss, and microglia activation in mice overexpressing mutant α-synuclein (7). However, other studies that have crossed LRRK2 knockout mice with different α-synuclein transgenic mice did not observe robust protection fr...

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Section: Resultssupporting

confidence: 74%

mentioning

confidence: 99%

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Daher

Volpicelli‐Daley

Blackburn

et al. 2014

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

198

208

View full text Add to dashboard Cite

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“…Thus, loss of dopaminergic neurons in models of Parkinson disease is completely prevented in MHC class II knockout mice as compared with wild-type mice. 21 MHC class II knockout mice likewise show reduced CNS pathology in a model of globoid cell leukodystrophy. 20 Furthermore, strain-dependent differences in susceptibility to various CNS conditions have been linked to differential expression of the RT1B chain of MHC II.…”

Section: Discussionmentioning

confidence: 95%

“…Furthermore, mouse MHC II knockout models demonstrate reduced axonal injury in EAE 19 and globoid cell leukodystrophy, 20 and minimal dopaminergic neuron loss in a model of Parkinson disease. 21 The combined data suggest that MHC II expression triggers a greater vulnerability to CNS injury.…”

mentioning

confidence: 99%

Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

Chidlow

Ebneter

Wood

et al. 2016

Journal of Glaucoma

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Aim: We acquired age-matched and sex-matched Sprague-Dawley rats from 2 independent breeding establishments. Serendipitously, we observed that constitutive, and bacterial toxin-induced, expression of major histocompatibility complex (MHC) class II RT1B chain in the uveal tract was much lower in one of the cohorts. Activated microglia are known to upregulate MHC II RT1B expression during optic nerve (ON) degeneration induced by raised intraocular pressure (IOP). We investigated whether, in a model of experimental glaucoma, microglial upregulation of MHC II RT1B was less efficacious and ON degeneration correspondingly less severe in the cohort of rats with low MHC II RT1B expression.Methods: Experimental glaucoma was induced by lasering the trabecular meshwork using a standard protocol. After 2 weeks of elevated IOP, retinal ganglion cells (RGC) survival, ON degeneration, and microglial responses were determined in both cohorts of rats.Results: Raised IOP-induced expression of MHC II RT1B by microglia was muted in the "Low" cohort compared with the "High" cohort. Axonal degeneration, RGC loss, and microgliosis were all significantly lower in the cohort of rats with low basal and induced expression of MHC II RT1B, despite both cohorts displaying IOP responses that were indistinguishable in terms of peak IOP and IOP exposure.Conclusions: Expression of MHC II RT1B by activated microglia in the ON during experimental glaucoma was associated with more severe RGC degeneration. Further studies are needed to elucidate the role of MHC II during experimental glaucoma.

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“…Also proteins like alpha‐synuclein (α‐synuclein), which has long been implicated in the pathogenesis of PD (Polymeropoulos et al, 1997) could act as both modulators of glial functions and as antigens themselves activating the peripheral and central immune system (Harms et al, 2013; Reynolds et al, 2008; Sanchez‐Guajardo et al, 2015). Thus in PD itself, α‐synuclein itself might be an antigen used by MHC II during antigen presentation and thus leading to the observed glial infiltration in PD (Hunot and Hirsch, 2003).…”

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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MHCII Is Required for -Synuclein-Induced Activation of Microglia, CD4 T Cell Proliferation, and Dopaminergic Neurodegeneration

Cited by 326 publications

References 39 publications

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

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

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