Intercellular transfer of prion in prion disease

朊病毒病中朊病毒的细胞间转移

• 批准号: 6601359
• 负责人: MAN-SUN M SY
• 金额: $ 34.94万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6601359
• 关键词: astrocytes; cell cell interaction; cell line; chemical aggregate; clinical research; communicable disease transmission; drug administration routes; genetically modified animals; glycosylphosphatidylinositols; green fluorescent proteins; human tissue; laboratory mouse; neurons; prions; protein transport; spleen; spongiform encephalopathy

DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathies (TSE) or prion diseases are a group of fatal neuro-degenerative disorders that affect both humans and animals. Most human TSE are sporadic, and about 10-15% of the cases are inherited as autosomal dominant traits. However, in several hundred cases, human TSE have been shown to be acquired by infection, which may be caused either by medical manipulations as in iatrogenic Creutzfeldt- Jakob Disease (CJD), or from the consumption of contaminated foods, as in kuru and variant CJD (vCJD). All prion diseases are believed to share the same pathogenic mechanism based on the conversion of the normal cellular prion (PrP c) into the infectious scrapie prion (prpSc). In animal TSE, such as scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle, it is believed that the PrP sc enters the host through the gastrointestinal tract, migrates to the spleen, and eventually causes disease in the CNS. However, in experimentally infected animals, PrP sc is first detected in the spleen even if the PrP Scis injected directly into the brain. The mechanism by which PrP sc moves in and out of the CNS is not known. Both PrP c and PrP sc are anchored to the membrane by glycosylphosphatidylinositol (GPI). Under some experimental conditions GPIanchored proteins can move from cell-to-cell. We hypothesize that inter-cellular transfer of PrP c or PrP sc facilitates the spread of infection. We developed a cell model to test whether PrP c is transfer from a human neuroblastoma cell line to a leukemia cell line, which lacks PrP c. We found that PrP c transfer requires cellular activation, cell-cell contact and is GPI anchor dependent. These findings strengthen the possibility that intercellular transfer of PrP c or PrP sc may play a role in the propagation of PrP L We propose: 1) to further characterize the intercellular transfer of prpC; 2) to investigate whether a similar transfer takes place for prpS; and 3) to explore whether intercellular transfer of PrP is important in the pathogenesis of prion disease in vivo using transgenic animals. The studies that we propose address very important and under studied aspects of prion diseases. The mechanisms that govern PrP sc propagation at the cellular level is one of the major remaining barriers to fully understanding the pathogenesis of prion diseases. New insights into this area will also lead to designs of more rational and effective treatment for prion diseases.

描述（由申请人提供）：传染性海绵状脑病（TSE）或朊病毒病是一组影响人类和动物的致命神经退行性疾病。大多数人类 TSE 是散发性的，大约 10-15% 的病例是常染色体显性遗传。然而，在数百例病例中，人类 TSE 已被证明是通过感染获得的，这可能是由医疗操作引起的，如医源性克雅氏病 (CJD)，也可能是由于食用受污染的食物引起的，如库鲁病和变异型克雅氏病 (vCJD)。据信，所有朊病毒疾病都具有相同的致病机制，即正常细胞朊病毒 (PrP c) 转化为传染性瘙痒病朊病毒 (prpSc)。在动物 TSE 中，例如绵羊痒病和牛海绵状脑病 (BSE)，人们认为 PrP sc 通过胃肠道进入宿主，迁移到脾脏，最终引起中枢神经系统疾病。然而，在实验感染的动物中，即使 PrP Scis 直接注射到大脑中，PrP sc 首先在脾脏中检测到。 PrP sc 进出 CNS 的机制尚不清楚。 PrP c 和 PrP sc 均通过糖基磷脂酰肌醇 (GPI) 锚定在膜上。在某些实验条件下，GPI锚定蛋白可以在细胞之间移动。我们假设 PrP c 或 PrP sc 的细胞间转移促进了感染的传播。我们开发了一个细胞模型来测试 PrP c 是否从人神经母细胞瘤细胞系转移到缺乏 PrP c 的白血病细胞系。我们发现 PrP c 转移需要细胞激活、细胞与细胞接触并且依赖于 GPI 锚。这些发现增强了 PrP c 或 PrP sc 的细胞间转移可能在 PrP L 的增殖中发挥作用的可能性。我们建议：1）进一步表征 prpC 的细胞间转移； 2) 调查prpS是否发生类似的转移； 3) 利用转基因动物探讨 PrP 的细胞间转移对于体内朊病毒病的发病机制是否重要。我们提出的研究涉及朊病毒疾病的非常重要且正在研究的方面。在细胞水平上控制 PrP sc 传播的机制是充分了解朊病毒疾病发病机制的主要障碍之一。对这一领域的新见解也将导致设计出更合理、更有效的朊病毒疾病治疗方法。