Biology of Prion Protein and the TSE Diseases

Pron病或传染性海绵状脑病是人和动物的传染性神经退行性疾病。Prion病的一个主要特征是将正常的宿主蛋白Prion蛋白(PrP)折叠和聚集成疾病相关的蛋白酶抵抗形式(PrPres)，可能导致脑损伤或传染性海绵状脑病是人和动物的传染性神经退行性疾病。Prion病的一个主要特征是将正常的宿主蛋白Prion蛋白(PrP)折叠和聚集成疾病相关的蛋白酶抵抗形式(PrPres)，这可能会导致脑损伤。 在2020财年，我们使用RNA-SEQ技术、网络分析和层次聚类分析，扩展了我们关于星形胶质细胞和小胶质细胞在体内宿主防御普恩病毒疾病中的作用的研究，以比较感染普鲁恩病毒的小鼠和模拟接种普恩病毒的小鼠以及PLX5622治疗的普恩病毒感染小鼠大脑中的基因表达。RNA-seq和网络分析表明，小胶质细胞通过激活整合素CD11c/18来响应普恩病毒的感染，而不采用与其他神经退行性疾病模型相关的表达特征。相反，小胶质细胞在疾病过程的后期获得了另一种分子标记。此外，星形胶质细胞表达了一种标志性的基因模式，似乎是普恩病毒疾病所特有的。 我们还与用PLX5622治疗的普恩病毒感染的小鼠进行了比较，以评估在普恩病毒感染期间，小胶质细胞切除对星形胶质细胞基因表达的影响。在小胶质细胞存在的情况下，与A1和A2反应的星形胶质细胞相关的独特的转录物混合物在感染普恩病毒的小鼠的大脑中增加。小胶质细胞消融后，这种反应性星形胶质细胞的表达模式增强。因此，在感染Prion后，小胶质细胞似乎降低了A1/A2星形胶质细胞的总体反应，这可能有助于提高感染后的存活率。 综上所述，RNA-seq分析表明，在普里昂病期间，中枢神经系统内的300多个生物过程发生了失调。独特的小胶质细胞和星形胶质细胞相关的表达特征在普恩病毒感染期间被确定。此外，星形胶质细胞增生症和独特的星形胶质细胞相关表达特征与小胶质细胞的影响无关。

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.