Interferon-gamma mediates neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy (MSA)

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Multiple system atrophy (MSA) is a fatal, progressive neurodegenerative disease that is characterized by demyelination in the corpus callosum and putamen due to the accumulation of alpha synuclein (α-syn) in glial cytoplasmic inclusions (GCI) within the oligodendrocytes. Previous data has shown that in post-mortem MSA brain, α-syn pathology is accompanied by MHCII expression and increased infiltration of peripheral T cells (CD4+). IFNγ released from CD4+ T cells enhances inflammation by binding to its receptor (IFNγR1) and, through the JAK/STAT pathway, activates MHCII antigen presentation. Other studies have shown, the neuroinflammation found in post-mortem tissue from MSA patients can be modeled in rodents through a modified AAV, Olig001-SYN which has a high tropism (>95%) for oligodendrocytes. Moreover, the Oligo001-SYN rodent model of MSA shows a similar robust CD4+ T cell response due to the oligodendrocyte α-syn expression. My preliminary results showed there was significant neuroinflammation via increase in IFNɣ and MHCII expression in the Olig001 mouse model. Additionally, when IFNɣ was knocked down there was a significant reduction in overall MHCII expression and general neuroinflammation and demyelination. IFNɣ is required for neuroinflammation and demyelination, however the cell specificity of IFNɣ remains unclear. Therefore, findings from this proposal can address if Th1 cells (CD4+ T cells that produce IFNɣ) are required for MSA pathology.