Biology of Prion Protein and the TSE Diseases

朊病毒蛋白的生物学和 TSE 疾病

• 批准号: 10697669
• 负责人: Bruce Chesebro
• 金额: $ 103.18万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697669
• 关键词: Adult; Agonist; Amyloid; Amyloid deposition; Animals; Appearance; Astrocytes; Biology; Brain; Brain Injuries; Cells; Cluster Analysis; Cone; Deposition; Disease; Gene Expression; Host Defense; Human; Human Development; Individual; Infection; Investigation; Mediating; Microglia; Modeling; Mus; Mutation; Neonatal; Nervous System; Neurodegenerative Disorders; Pathway Analysis; Peptide Hydrolases; Photoreceptors; PrP; PrPSc Proteins; Prevention strategy; Prion Diseases; Prions; Process; Proteins; Resistance; Retina; Rod; Role; Scrapie; Senile Plaques; Site; System; TLR4 gene; TLR7 gene; Technology; Testing; Tissues; Vertebrate Photoreceptors; amyloid formation; brain cell; brain tissue; cofactor; design; human disease; in vivo; mutant; protein expression; response; tau Proteins; tau-1; transcriptome sequencing

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.

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) 重新折叠和聚集成疾病相关的蛋白酶抗性形式 (PrPres)，这可能会导致脑损伤。 在 2020、21 和 22 财年，我们利用 RNA-seq 技术、网络分析和层次聚类分析，扩展了星形胶质细胞和小胶质细胞在宿主体内防御朊病毒疾病中作用的研究，以比较感染朊病毒的大脑中的基因表达与模拟的朊病毒感染的大脑中的基因表达。 -接种的小鼠，以及经PLX5622处理的朊病毒感染的小鼠。 在 2022 财年，我们还研究了 PLX 5622 消除小胶质细胞对离体和体内新生儿和成人小胶质细胞对各种 TLR 激动剂反应的影响。结果表明，TLR7 介导的反应高度依赖于小胶质细胞，TLR4 和 TLR9 的反应部分依赖于小胶质细胞。因此，这些 TLR 可能在小胶质细胞对体内瘙痒病的抑制作用中发挥重要作用。 还在小鼠中研究了视网膜朊病毒感染，发现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约两周被感染和损坏，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 在视网膜中沉积的部位正在研究中，其损伤机制也在研究中。 在人类中，由于朊病毒蛋白突变形式的表达而导致的家族性朊病毒病的发展通常会导致脑组织中出现淀粉样朊病毒蛋白斑块，其中含有突变朊病毒蛋白和人磷酸化tau蛋白。在我们表达缺乏 GPI 锚定部分的 PrP 的模型中，朊病毒感染也会导致含有 PrP 的淀粉样斑块的形成。过去，我们曾尝试测试人 tau 蛋白的表达是否能够增加系统中的淀粉样斑块。培育小鼠以表达适当的蛋白质，然后用​​朊病毒感染。尽管观察到了斑块，但人类 tau 蛋白的存在似乎确实增加或减少了淀粉样蛋白沉积的过程。因此，tau蛋白可能不是这种疾病所需的辅助因子。