RT Journal Article
SR Electronic
T1 IFNγ drives neuroinflammation and demyelination in a mouse model of multiple system atrophy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.22.517543
DO 10.1101/2022.11.22.517543
A1 Gallups, Nicole J.
A1 Childers, Gabrielle M.
A1 Webster, Jhodi M.
A1 Zane, Asta
A1 Yang, Ya-Ting
A1 Mudium, Nikhita
A1 Manfredsson, Fredric P.
A1 Kordower, Jeffrey H.
A1 Harms, Ashley S.
YR 2022
UL http://biorxiv.org/content/early/2022/11/23/2022.11.22.517543.abstract
AB Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of GCI pathology, however it is not known what specifically drives disease pathogenesis. Recently in a mouse model of MSA, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs also remains unclear. In this study we use genetic and pharmacological approaches in a novel model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation and demyelination. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression in CD4 T cells drives α-syn-mediated neuroinflammation and demyelination, and strategies to target IFNγ expression may be a potential disease modifying therapeutic strategy for MSA.Competing Interest StatementThe authors have declared no competing interest.α-synalpha-synucleinAPCantigen presenting cellsGCIglial cytoplasmic inclusionsIFNγInterferon gammaIFNγR1interferon gamma receptor 1MHCIImajor histocompatibility complex IIMSAmultiple system atrophyPDParkinson’s disease