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

多系统萎缩(MSA)是一种致命的进行性神经退行性疾病，其特征是 因α-突触核蛋白(α-SYN)在胶质细胞中的积聚而导致的胼胝体和壳核的脱髓鞘 少突胶质细胞内可见胞浆内包涵体。先前的数据显示，在尸检中 脑部α-SYN病理伴有MHCII表达和外周T细胞浸润增多 (CD4+)。从CD4+T细胞释放的干扰素γ通过与其受体(干扰素γR1)结合来增强炎症， 通过JAK/STAT途径，激活MHCII抗原递呈。其他研究表明， 在MSA患者死后组织中发现的神经炎症可以通过改良的 对少突胶质细胞有很高趋向性(95%)的AAV，Orig001-SYN。此外，寡头001-SYN啮齿动物 由于少突胶质细胞α-SYN的表达，MSA模型显示出类似的强大的CD_4+T细胞反应。我的 初步结果显示，通过增加干扰素ɣ和mhcII的表达，出现了显著的神经炎症。 在Orig001小鼠模型中。此外，当干扰素ɣ被击倒时， 总的MHCII表达和一般神经炎和脱髓鞘。干扰素ɣ是必需的 神经炎症和脱髓鞘，然而干扰素ɣ的细胞特异性仍不清楚。因此，调查结果 这项建议可以解决是否需要Th1细胞(产生干扰素ɣ的CD_4+T细胞)来进行多发性硬化症病理。

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.