Biology of Prion Protein and the TSE Diseases

朊病毒病或传染性海绵状脑病是人类和动物的传染性神经退行性疾病。朊病毒疾病的一个主要特征是正常宿主蛋白朊病毒蛋白（PrP）的重新折叠和聚集，形成疾病相关的蛋白酶抗性形式（PrPres），这可能导致脑损伤。朊病毒疾病或传染性海绵状脑病是人类和动物的感染性神经退行性疾病。朊病毒疾病的一个主要特征是正常宿主蛋白朊病毒蛋白（PrP）重新折叠和聚集成疾病相关的蛋白酶抗性形式（PrPres），这可能导致脑损伤。

Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. In FY20, we extended our studies of the role of astroglia and microglia in host defense against prion disease in vivo using RNA-seq technology, network analysis, and hierarchical cluster analysis to compare gene expression in brains of prion-infected versus mock-inoculated mice, as well as PLX5622-treated prion-infected mice. RNA-seq and network analysis suggested that microglia responded to prion infection through activation of integrin CD11c/18 and did not adopt the expression signature associated with other neurodegenerative disease models. Instead, microglia acquired an alternative molecular signature late in the disease process. Furthermore, astrocytes expressed a signature pattern of genes which appeared to be specific for prion diseases. Comparisons were also made with prion-infected mice treated with PLX5622 to assess the impact of microglia ablation on astrocyte gene expression during prion infection. In the presence of microglia, a unique mix of transcripts associated with A1- and A2-reactive astrocytes was increased in brains of prion-infected mice. After ablation of microglia, this reactive astrocyte expression pattern was enhanced. Thus, after prion infection, microglia appeared to decrease the overall A1/A2-astrocyte responses which might contribute to increased survival after infection. In summary, RNA-seq analysis indicated dysregulation of over 300 biological processes within the CNS during prion disease. Distinctive microglia- and astrocyte-associated expression signatures were identified during prion infection. Furthermore, astrogliosis and the unique astrocyte-associated expression signature were independent of microglial influences.