MHCII is required for α-Synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration

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

Research output: Contribution to journalArticlepeer-review

198 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9592-9600
Number of pages9
JournalJournal of Neuroscience
Volume33
Issue number23
DOIs
StatePublished - Jun 7 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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