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Articles, Neurobiology of Disease

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

Ashley S. Harms, Shuwen Cao, Amber L. Rowse, Aaron D. Thome, Xinru Li, Leandra R. Mangieri, Randy Q. Cron, John J. Shacka, Chander Raman and David G. Standaert
Journal of Neuroscience 5 June 2013, 33 (23) 9592-9600; DOI: https://doi.org/10.1523/JNEUROSCI.5610-12.2013
Ashley S. Harms
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology,
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Shuwen Cao
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology,
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Amber L. Rowse
2Department of Microbiology, and
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Aaron D. Thome
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology,
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Xinru Li
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology,
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Leandra R. Mangieri
3Department of Pathology, Neuropathology Division, The University of Alabama at Birmingham, Birmingham, Alabama 35294,
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Randy Q. Cron
4Department of Pediatrics, Division of Rheumatology, Children's Hospital of Alabama, Birmingham, Alabama 35294,
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John J. Shacka
3Department of Pathology, Neuropathology Division, The University of Alabama at Birmingham, Birmingham, Alabama 35294,
5The Birmingham VA Medical Center, Birmingham, Alabama 35294, and
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Chander Raman
6Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294
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David G. Standaert
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology,
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Abstract

Accumulation of α-synuclein (α-syn) in the brain is a core feature of Parkinson disease (PD) and leads to microglial activation, production of inflammatory cytokines and chemokines, T-cell infiltration, and neurodegeneration. Here, we have used both an in vivo mouse model induced by viral overexpression of α-syn as well as in vitro systems to study the role of the MHCII complex in α-syn-induced neuroinflammation and neurodegeneration. We find that in vivo, expression of full-length human α-syn causes striking induction of MHCII expression by microglia, while knock-out of MHCII prevents α-syn-induced microglial activation, antigen presentation, IgG deposition, and the degeneration of dopaminergic neurons. In vitro, treatment of microglia with aggregated α-syn leads to activation of antigen processing and presentation of antigen sufficient to drive CD4 T-cell proliferation and to trigger cytokine release. These results indicate a central role for microglial MHCII in the activation of both the innate and adaptive immune responses to α-syn in PD and suggest that the MHCII signaling complex may be a target of neuroprotective therapies for the disease.

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The Journal of Neuroscience: 33 (23)
Journal of Neuroscience
Vol. 33, Issue 23
5 Jun 2013
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MHCII Is Required for α-Synuclein-Induced Activation of Microglia, CD4 T Cell Proliferation, and Dopaminergic Neurodegeneration
Ashley S. Harms, Shuwen Cao, Amber L. Rowse, Aaron D. Thome, Xinru Li, Leandra R. Mangieri, Randy Q. Cron, John J. Shacka, Chander Raman, David G. Standaert
Journal of Neuroscience 5 June 2013, 33 (23) 9592-9600; DOI: 10.1523/JNEUROSCI.5610-12.2013

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MHCII Is Required for α-Synuclein-Induced Activation of Microglia, CD4 T Cell Proliferation, and Dopaminergic Neurodegeneration
Ashley S. Harms, Shuwen Cao, Amber L. Rowse, Aaron D. Thome, Xinru Li, Leandra R. Mangieri, Randy Q. Cron, John J. Shacka, Chander Raman, David G. Standaert
Journal of Neuroscience 5 June 2013, 33 (23) 9592-9600; DOI: 10.1523/JNEUROSCI.5610-12.2013
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