PRION PROTEIN IN MINK ENCEPHALOPATHY

水貂脑病中的朊病毒蛋白

• 批准号: 2051899
• 负责人: RICHARD FLOYD MARSH
• 金额: $ 15.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-29 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2051899
• 关键词: amyloid proteins; cryostat; genetic strain; genetically modified animals; glycoprotein biosynthesis; glycosylation; hamsters; histopathology; immunocytochemistry; immunoprecipitation; infrared spectrometry; interferometry; laboratory mouse; neural degeneration; neurotropic virus; phosphorylation; posttranslational modifications; prions; protein degradation; protein isoforms; protein structure function; proteoglycan; spongiform encephalopathy; tissue /cell culture

The transmissible spongiform encephalopathies (TSEs) comprise a group of neurodegenerative diseases affecting both humans and animals. The TSEs are remarkable in that they appear to be caused by a host-encoded protein (the prion protein) that becomes modified in an as yet unknown way that reduces the host's capability to completely degrade the peptide and it accumulates as amyloid in the brain. Also, inherited forms of these diseases in humans have been associated with gene mutations causing changes in the primary amino acid sequence of the protein. Up to this point' there is considerable similarity between TSEs and AIzheimer's disease. However, most occurrences of TSEs are not inherited, but rather acquired by an apparent infectious process. Moreover, it is the protein itself that appears to be the transmissible agent. Research in this field is now focused on three main issues, (1)What is the nature of the posttranslational change that modifies the protein?, (2) By what mechanism does the modified protein convert its normal counterpart?, and ( 3) How can these changes account for distinct strains of these transmissible proteinaceous agents? This grant application proposes to continue studies on the physicochemical and biological properties of distinct strains of the transmissible mink encephalopathy (TME) agent. These hamster models of TME are unique in that they represent the first identification of individual strains of agent having distinct clinical and biological features, as well as producing prion proteins having different biochemical and physical properties. Because these diseases are produced in a single outbred species, differences in the disease-specific prion proteins (PrPTME) cannot be due to changes in primary amino acid sequence, but must be conveyed by properties of the proteins themselves. These observations emphasize the importance of the transmissible agent in determining the outcome of infection, independent of the PrP genotype of the host. This application proposes to examine the secondary structure of PrPTME by Fourier transform infrared spectroscopy. to study the biologic behavior of TME strains in various species of hamsters and in transgenic mice expressing the hamster prion protein gene, and to attempt to study the biosynthesis and degradation of PrPTME in infected brain slices. The results of these studies will be relevant to not only our understanding of the pathogenesis of TSEs, but also to other neurodegenerative disorders and may provide new insights into protein-protein interactions.

传染性海绵状脑病 (TSE) 包括一组 影响人类和动物的神经退行性疾病。 TSE 是 值得注意的是，它们似乎是由宿主编码的蛋白质（ 朊病毒蛋白）以一种目前未知的方式被修饰，从而减少 宿主完全降解肽并积累的能力 作为大脑中的淀粉样蛋白。此外，人类这些疾病的遗传形式 与导致原发性改变的基因突变有关 蛋白质的氨基酸序列。到目前为止，已经有相当多的 TSE 和艾茨海默氏病之间的相似性。然而，大多数情况 的 TSE 不是遗传性的，而是通过明显的感染获得的 过程。此外，蛋白质本身似乎是 传染媒介。 目前该领域的研究主要集中在三个问题上：（1）什么是 修饰蛋白质的翻译后变化的性质？, (2) 修饰后的蛋白质通过什么机制转化其正常对应物？ (3) 这些变化如何解释这些变化的不同菌株？ 传染性蛋白质制剂？本补助金申请建议 继续研究其理化和生物学特性 传染性水貂脑病（TME）病原体的不同菌株。 TME 的这些仓鼠模型是独一无二的，因为它们代表了第一个 鉴定具有不同临床和特征的个体菌株 生物学特征，以及产生具有不同的朊病毒蛋白 生化和物理特性。因为这些疾病产生于 单一近交物种，疾病特异性朊病毒的差异 蛋白质（PrPTME）不可能是由于一级氨基酸序列的变化， 但必须通过蛋白质本身的特性来传达。这些 观察结果强调了传播媒介的重要性 确定感染的结果，与 PrP 基因型无关 主人。 本申请提出通过以下方式检查 PrPTME 的二级结构： 傅里叶变换红外光谱。研究生物行为 各种仓鼠和转基因小鼠中的 TME 菌株 表达仓鼠朊病毒蛋白基因，并尝试研究 受感染脑切片中 PrPTME 的生物合成和降解。这 这些研究的结果不仅与我们的理解相关 TSE 的发病机制，也与其他神经退行性疾病和 可能为蛋白质-蛋白质相互作用提供新的见解。