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)，这可能会导致脑损伤。 在20财年、21财年和22财年，我们使用RNA-SEQ技术、网络分析和层级聚类分析，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。 在FY22财年，我们还研究了PLX 5622去除小胶质细胞对各种TLR激动剂体外和体内新生儿和成人小胶质细胞反应的影响。结果表明，TLR7介导的反应高度依赖于小胶质细胞，而TLR4和TLR9的反应部分依赖于小胶质细胞。因此，这些TLRs可能在体内小胶质细胞对瘙痒病的抑制作用中起重要作用。 在小鼠中也研究了Pron感染视网膜，发现其主要集中在感光细胞(视杆细胞和视锥细胞)上。视锥细胞在视杆细胞之前大约2周受到感染和损伤，但随后两种亚型的所有细胞都被破坏并从视网膜上移除。PrPSc在视网膜中的沉积位置正在研究中，损伤机制也在调查中。 在人类中，由于表达突变形式的Prion蛋白而导致的家族性Prion病的发展通常会导致在含有突变的Prion蛋白和人的磷酸化tau蛋白的脑组织中出现淀粉样Prion蛋白斑块。在我们的模型中，表达缺少GPI锚定部分的PrP，Prion感染也会导致含有PrP的淀粉样斑块的形成。在过去，我们曾试图测试人类tau蛋白的表达是否能够增加系统中的淀粉样斑块。培育出表达适当蛋白质的小鼠，然后感染普恩病毒。虽然观察到了斑块，但人tau的存在似乎确实增加或减少了淀粉样蛋白的沉积过程。因此，tau蛋白可能不是该病所需的辅助因子。

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, FY21 and FY22 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. In FY22, we also investigated effects of microglial depletion by PLX 5622 on the responses to various TLR agonists by ex vivo and in vivo neonatal and adult microglia. Results indicated that TLR7 mediated responses were highly dependent on microglia, and TLR4 and TLR9 responses were partially dependent on microglia. Thus, these TLRs might be important in the inhibitory effects of microglia on scrapie disease in vivo. Prion infection of retina was also studied in mice, and was found to be focused mostly on photoreceptor cells (rods and cones). Cones were infected and damaged about 2 weeks prior to rods, but subsequently all the cells of both subtypes were destroyed and removed from the retina. The sites of PrPSc deposition in retina are being studied and the mechanisms of damage are also under investigation. In humans, development of familial prion disease due expression of mutant forms of prion protein usually leads to appearance of amyloid prion protein plaques in brain tissue containing both mutant prion protein and human phosphorylated tau protein. In our model expressing PrP lacking the GPI anchor moiety, prion infection also results in formation of amyloid plaques containing PrP. In the past we have attempted to test whether expression of human tau protein was able to increase amyloid plaques in the system. Mice were bred to express the appropriate proteins and then infected with prions. Although plaques were observed, the presence of human tau did appear to increase or decrease the process of amyloid deposition. Therefore, tau protein may not be a cofactor required in this disease.