Intercellular transfer of prion in prion disease

描述（由申请人提供）：传染性海绵状脑病（TSE）或朊病毒疾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是散发的，约10-15%的病例以常染色体显性特征遗传。然而，在数百例病例中，已证明人类TSE是通过感染获得的，这可能是由医疗操作引起的，如医源性克雅病（CJD），也可能是由食用受污染的食物引起的，如库鲁病和变异型克雅病（vCJD）。基于正常细胞朊病毒（PrP c）转化为传染性痒病朊病毒（prpSc），所有朊病毒疾病被认为具有相同的致病机制。在动物TSE中，如羊痒病和牛海绵状脑病（BSE）， PrP sc被认为是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，即使将PrP sc直接注射到大脑中，也首先在脾脏中检测到PrP sc。PrP sc进出中枢神经系统的机制尚不清楚。PrP c和PrP sc通过糖基磷脂酰肌醇（GPI）锚定在细胞膜上。在一些实验条件下，gpianchoring蛋白可以在细胞间移动。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的转移需要细胞活化、细胞间接触并且依赖于GPI锚定。这些发现加强了prpC或prpsc在prpl繁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)调查是否有类似的转移发生在prpS；3)利用转基因动物探讨PrP在体内的细胞间转移是否在朊病毒疾病的发病机制中起重要作用。我们提出的研究解决了朊病毒疾病中非常重要和尚待研究的方面。在细胞水平上控制PrP sc繁殖的机制是充分了解朊病毒疾病发病机制的主要障碍之一。在这一领域的新见解也将导致设计更合理和有效的治疗朊病毒疾病。

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.