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IFNγ drives neuroinflammation and demyelination in a mouse model of multiple system atrophy

Gallups, N. J.; Childers, G. M.; Webster, J. M.; Yang, Y.-T.; Zane, A.; Mudium, N.; Manfredsson, F.; Kordower, J.; Harms, A. S.

2022-11-23 neuroscience
10.1101/2022.11.22.517543 bioRxiv
Show abstract

Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (-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 (IFN{gamma}) drives neuroinflammation and demyelination. Furthermore, using an IFN{gamma} reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFN{gamma} in response to -syn overexpression in oligodendrocytes. Results from these studies indicate that IFN{gamma} expression in CD4 T cells drives -syn-mediated neuroinflammation and demyelination, and strategies to target IFN{gamma} expression may be a potential disease modifying therapeutic strategy for MSA.

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