Abstract
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 Statement
The authors have declared no competing interest.
Abbreviations
- α-syn
- alpha-synuclein
- APC
- antigen presenting cells
- GCI
- glial cytoplasmic inclusions
- IFNγ
- Interferon gamma
- IFNγR1
- interferon gamma receptor 1
- MHCII
- major histocompatibility complex II
- MSA
- multiple system atrophy
- PD
- Parkinson’s disease