title: MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration.
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.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Harms
authors.forename: Shuwen
authors.initials: S
authors.lastname: Cao
authors.forename: Amber L
authors.initials: AL
authors.lastname: Rowse
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Thome
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
authors.forename: Leandra R
authors.initials: LR
authors.lastname: Mangieri
authors.forename: Randy Q
authors.initials: RQ
authors.lastname: Cron
authors.forename: John J
authors.initials: JJ
authors.lastname: Shacka
authors.forename: Chander
authors.initials: C
authors.lastname: Raman
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005802:Genes, MHC Class II / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000096:biosynthesis*
chemical_list: D051844:alpha-Synuclein