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性神经退行性疾病。大多数人类TSE是散发性的，约10-15%的病例是以常染色体显性遗传。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），或由食用受污染的食物引起的，如库鲁病和变异型克雅氏病（vCJD）。所有的朊病毒疾病被认为共享相同的致病机制，基于正常细胞朊病毒（PrPc）转化为传染性羊瘙痒症朊病毒（prpSc）。在动物TSE中，如绵羊的瘙痒症和牛的牛海绵状脑病（BSE），据信PrP sc通过胃肠道进入宿主，迁移到脾脏，并最终导致CNS疾病。然而，在实验感染的动物中，即使将PrP Scis直接注射到脑中，也首先在脾脏中检测到PrP sc。PrP sc进出CNS的机制尚不清楚。PrPc和PrPsc都是通过糖基磷脂酰肌醇（GPI）锚定在膜上的。在某些实验条件下，GPI锚定的蛋白质可以在细胞间移动。我们推测PrP c或PrP sc的细胞间转移促进了感染的传播。我们建立了一个细胞模型来检测PrPc是否从人神经母细胞瘤细胞系转移到缺乏PrPc的白血病细胞系。我们发现PrPc的转移需要细胞活化、细胞-细胞接触，并且是GPI锚依赖性的。这些发现加强了PrPc或PrPsc的细胞间转移可能在PrPL的传播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）使用转基因动物探索PrP的细胞间转移在体内朊病毒病的发病机制中是否重要。我们提出的研究解决了朊病毒疾病非常重要和研究不足的方面。在细胞水平上控制朊蛋白SC传播的机制是充分理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.