MHCII Is Required for -Synuclein-Induced Activation of Microglia, CD4 T Cell Proliferation, and Dopaminergic Neurodegeneration
Open accessAbstract
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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MHC-II expression on activated microglia is associated with proinflammatory cytokine release of TNF-α, IL-1β, and CD80.
“MHC-II expression on activated microglia has been shown to be associated with proinflammatory cytokine release of TNF-α, IL-1β, and CD80 [36, 37].”
From Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice (2019) · cites this paper as [36]
The section on α-synuclein-induced CD4 T-cell proliferation and cytokines (page unavailable) reports increased TNF and IL-1β production when treated microglia were cocultured with CD4 T cells. It does not report CD80 release, and microglia alone did not show a significant inflammatory response under the tested conditions. The claim therefore omits the T-cell interaction required for the reported cytokine response and adds an unsupported CD80 component. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMHCII expression precedes and regulates dopaminergic neurodegeneration in the substantia nigra.
“Furthermore, MHCII expression precedes and regulates dopaminergic neurodegeneration in the substantia nigra [94,95,96].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [96]
Overexpression of α-syn can induce MHC-II expression by microglia.
“In vivo and in vitro studies have demonstrated that overexpression of α-syn can induce the MHC-II expression by microglia.”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Harms et al., 2013
MHC-II expression in microglia can play an important role in innate and adaptive immune responses in PD.
“The MHC-II expression in microglia cells can play an important role in the immune responses (innate and adaptive) in PD (Michelucci et al., 2009; Harms et al., 2013; Gonzalez et al., 2015).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Harms et al., 2013
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References 39 · Cited by 406
- Authors
- Harms, A. S., Cao, S., Rowse, A. L., Thome, A. D., Li, X., Mangieri, L. R., Cron, R. Q., Shacka, J. J., Raman, C., & Standaert, D. G.
- Affiliations
- University of Alabama at Birmingham (US)
- ORCID
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-06-05
- Volume
- 33
- Issue
- 23
- Pages
- 9592-9600
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3903980
- OpenAlex
- W2025810715
- Cited by
- 406
- References
- 39
- Citations by year
- 2026: 24 · 2025: 27 · 2024: 58 · 2023: 36 · 2022: 42 · 2021: 43 · 2020: 32 · 2019: 27 · 2018: 33 · 2017: 23 · 2016: 19 · 2015: 20 · 2014: 21 · 2013: 1
- FWCI
- 11.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Alabama
- National Institutes of Health (P30 AR48311)
- National Institute of Allergy and Infectious Diseases (R01AI076562)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007450, P30AR048311, P30 AR 48311)
- National Center for Research Resources (G20RR022807, G20RR025858)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- MHC class II, alpha-synuclein, Parkinson's disease, microglial activation, dopaminergic neuron loss, CD4+ T cell proliferation, antigen presentation, neuroinflammation, IgG deposition, neuroprotection
- MeSH terms
- Animals, Animals, Newborn, Cells, Cultured, Genes, MHC Class II, Humans, Male, Mice, Inbred C57BL, Nerve Degeneration, Parkinson Disease, CD4-Positive T-Lymphocytes, Microglia, Mice, Knockout, Cell Proliferation, Mice, alpha-Synuclein, Dopaminergic Neurons
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