Intercellular transfer of prion in prion disease

描述(申请人提供)：传染性海绵状脑病(TSE)或普恩疾病是一组致命的神经退行性疾病，对人类和动物都有影响。大多数人类TSE是散发性的，大约10%-15%的病例是作为常染色体显性遗传的。然而，在数百个病例中，人类TSE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)，或因食用受污染的食物，如库鲁病和变异型CJD(VCJD)。所有的PrP疾病都有相同的致病机制，其基础是正常细胞内的Prion(PrPc)转化为传染性的瘙痒病毒(PrpSc)。在动物TSE中，如绵羊的瘙痒病和牛的牛海绵状脑病(BSE)，人们认为PrP sc通过胃肠道进入宿主，迁移到脾，最终导致中枢神经系统的疾病。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也首先在脾中被检测到。PrP sc进出中枢神经系统的机制尚不清楚。PrP-c和PrP-sc都是通过糖基磷脂酰肌醇(GPI)固定在膜上的。在某些实验条件下，GPI型锚定蛋白可以在细胞间移动。我们假设PrPc或PrPsc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测试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转移需要细胞激活，细胞间的接触，并且是GPI锚依赖的。这些发现证实了PrP c或PrP sc的细胞间转移可能在PrP的增殖中起作用的可能性。L建议：1)进一步研究PrPC的细胞间转移；2)研究PrP是否也发生了类似的转移；3)利用转基因动物来探索PrP的细胞间转移是否在体内PrP疾病的发病机制中起重要作用。我们提出的研究解决了普恩病毒疾病中非常重要和未被研究的方面。在细胞水平上控制PrP-sc传播的机制是完全理解PrP-sc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、更有效的普恩病毒疾病治疗方法。

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.