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

Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (alpha-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing alpha-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFN gamma) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFN gamma reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFN gamma in response to alpha-syn overexpression in oligodendrocytes. Results from these studies indicate that IFN gamma expression from CD4+ T cells drives alpha-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFN gamma expression may be a potential disease modifying therapeutic strategy for MSA.