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朊病也称传染性海绵状脑病,目前研究认为主要由3种原因引起:一是遗传性因素:由于编码PrPc的基因发生致病性突变所造成;二是后天获得性因素:由外源性的朊病毒感染引起;三是散发性因素:由不明原因造成.朊病是由朊病毒(即PrPSc)所引起,朊病毒能够自我复制,而且具有蛋白酶抗性,是目前惟一确定的病原因子.PrPSc的复制是通过正常细胞朊蛋白即PrPc转变而来. 相似文献
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就细胞型朊蛋白PrP^c的分子生物学特性、朊蛋白的生理功能、致病性朊蛋白PrP^sc对免疫系统的影响、朊病毒的外周致病机理以及相关细胞因子、化学因子与朊病毒神经侵袭之间的关系、朊病毒从外周到中枢的转运机制、入侵门户、血液传播及朊病的其他病理标志和检测方法的研究做一综述。 相似文献
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异常朊蛋白(P rP sc)是一种可引起人和动物传染性脑退化病的不含核酸的蛋白因子。P rP c是一个正常的蛋白,有正常的生理功能,主要分布于神经元表面,属于肌醇磷脂锚蛋白类。由P rP c向P rP sc转变即产生疾病。作者简单介绍了正常和异常朊蛋白结构、功能、构象改变及朊病毒种属屏障的研究进展,并提出了目前尚待研究的问题。 相似文献
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朊病毒是一种感染性蛋白质,能引起一系列的被称为传染性海绵状脑病(TSEs)或朊病毒病的致命性神经变性型疾病.在哺乳动物中,朊病毒通过招募普通的细胞蛋白(PrPc)并诱导其转化为具有致病性的PrPsc而实现自我复制.最近的研究结果表明,抗朊病毒的抗体能永久性地治愈被朊病毒感染的细胞.但是,全长的抗体和蛋白质不能通过血脑屏障(BBB),这妨碍了将其用于TSEs的体内治疗.采用另一种方式,即通过腺联病毒(AAV)转导将有朊病毒特异性的scFv传递到大脑内,尽管这不能完全保护其不受感染,但能延迟受感染小鼠的发病时间.通过直接向细胞培养物中加入羊痒病病毒或使用慢病毒和腺联病毒双转导载体使其感染,作者研究了重组的抗PrP(D18)单链可变片段(scFv)抗朊病毒的效果.结果表明,在感染细胞中重组的抗PrP scFv能够减少蛋白酶K的含量.另外,证实了与AAV相比,慢病毒能更有效的使抗PrP scFv基因转染并减少感染的神经元细胞中PrPsc的含量.最后,作者使用生物信息学的方法构建了D18scFv-PrP复合物的结构模型.有趣的是,根据反馈的结果,在D18scFv将PrPc锚定到抗体凹槽过程中,ArgPrP151(朊蛋白的第151位氨基酸)是一个关键的氨基酸残基.以上结果表明,将靶向PrP的被动和主动的免疫方法相结合,可能是治疗干预朊病毒病的一个可行策略. 相似文献
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朊病毒是一种感染性蛋白质,能引起一系列的被称为传染性海绵状脑病(TSEs)或朊病毒病的致命性神经变性型疾病。在哺乳动物中,朊病毒通过召募普通的细胞蛋白(PrPc)并诱导其转化为具有致病性的PrPsc而实现自我复制。最近的研究结果表明,抗朊病毒的抗体能永久性地治愈被朊病毒感染的细胞。但是,全长的抗体和蛋白质不能通过血脑屏障(BBB),这妨碍了将其用于TSEs的体内治疗。采用另一种方式,即通过腺联病毒(AAV)转导将有朊病毒特异性的scFv传递到大脑内,尽管这不能完全保护其不受感染,但能延迟受感染小鼠的发病时间。通过直接向细胞培养物中加入羊痒病病毒,或使用慢病毒和腺联病毒双转导载体使其感染,作者研究了重组的抗PrP(D18)单链可变片段(scFv)抗朊病毒的效果。结果表明,在感染细胞中重组的抗PrP scFv能够减少蛋白酶K的含量。另外,证实了与AAV相比,慢病毒能更有效的使抗PrP scFv基因转染并减少感染的神经元细胞中PrPsc的含量。最后,作者使用生物信息学的方法构建了D18scFv-PrP复合物的结构模型。有趣的是,根据反馈的结果,在D18scFv将PrPc锚定到抗体凹槽过程中,ArgPrP151(朊蛋... 相似文献
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Sipos W Kraus M Schmoll F Achmann R Baumgartner W 《Journal of veterinary medicine. A, Physiology, pathology, clinical medicine》2002,49(8):415-418
Scrapie, an ovine and caprine transmissible spongiforme encephalopathy, is widely spread among sheep populations in many European countries. As it is known that susceptibility to scrapie is determined genetically, breeding programmes aiming at providing scrapie-resistant flocks have been established. Selection is based on the prion protein (PrP) genotype, which is used to classify animals into risk groups of susceptibility (R1-R5) according to the amino acids encoded by codons at positions 136, 154 and 171, respectively. At position 136 (136V-->136A) alanine and at position 154 (154H-->154R) as well as 171 (171Q-->171R) arginine are the favoured amino acids. Whereas PrP genotyping data are available for many of the European sheep breeds, comparable data for local Austrian sheep breeds are missing. The most known among these are Tyrolean mountain sheep, forest sheep. Tyrolean stone sheep and Carynthian sheep. The genotypes of 112 sheep from these four local breeds were determined. In terms of PrP genetics, Austrian breeds belong to the group of non-valine-breeds, with the exception of the Carynthian sheep, that exhibited a frequency of 136V of 4.2%. The most frequent allele was ARQ with 64.6-71.2% (depending on the breed), followed by ARR (14.8-25.8%). In contrast to the above-mentioned findings, scrapie has never been diagnosed in any of the Austrian sheep breeds. Native Austrian sheep breeds exhibit a very robust constitution, a pronounced adaptation to harsh climates and good reproduction parameters as well as a marked mother instinct. Therefore, these breeds are often used in crossbreeding programmes. Beside the above-mentioned characteristics, our results indicate that the investigated breeds may be effectively used in crossing-out breeding programmes for eliminating valine at position 136 of PrP. 相似文献
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Goldmann W 《Veterinary research》2008,39(4):30
Scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) are prion diseases in ruminants with considerable impact on animal health and welfare. They can also pose a risk to human health and control is therefore an important issue. Prion protein (PrP) genetics may be used to control and eventually eradicate animal prion diseases. The PrP gene in sheep and other representatives of the order Artiodactyles has many polymorphisms of which several are crucial determinants of susceptibility to prion diseases, also known as transmissible spongiform encephalopathies (TSE). This review will present the current understanding of PrP genetics in ruminants highlighting similarity and difference between the species in the context of TSE. 相似文献
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Prion diseases are fatal neurodegenerative infectious disorders for which no therapeutic or prophylactic regimens exist. Our work aims to eliminate PrP(c) as substrate for the conversion into PrP(Sc) and to increase the cellular clearance capacity of PrP(Sc). In order to achieve the first objective, we used chemical compounds which interfere with the subcellular trafficking of PrP(c), e.g. by intracellular re-routing. Recently, we found that PrP(c) requires cholesterol for cell surface localisation. Treatment with mevinolin significantly reduced the amount of cell surface PrP(c) and led to its accumulation in the Golgi compartment. These data show that cholesterol is essential for the cell surface localisation of PrP(c), which is in turn known to be necessary for the formation of PrP(Sc). Another anti-prion strategy uses RNA and peptide aptamers directed against PrP(c). We have selected peptide aptamers using a constrained peptide library presented on the active site loop of the Escherichia coli protein TrxA in a Y2H screen. Several peptides reproducibly binding to PrP(c) in several assays were identified. Preliminary data indicate that selected peptide aptamers are able to interfere with prion propagation in prion-infected cells. To obtain additive effects we have tried to clarify cellular mechanisms that enable cells to clear prion infectivity. This goal was achieved by selective interference in intracellular signalling pathways which apparently also increase the cellular autophagy machinery. Finally, we have tried to establish an active auto-vaccination approach directed against PrP, which gave some positive preliminary results in the mouse system. This might open the door to classical immunological interference techniques. 相似文献
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Classical scrapie has proved to be a notoriously difficult disease to control due to a poor understanding of its natural history. The recognition of disease risk linkage to PrP genotype has offered the prospect of a disease control strategy, viz. genotyping and selective breeding, novel to veterinary medicine when first considered in the 1990s. The UK Spongiform Encephalopathy Advisory Committee recommended the exploitation of this approach in a voluntary, national programme to control classical scrapie and protect the public against food-borne exposure to bovine spongiform encephalopathy, should the national flock have been exposed via contaminated feed. The National Scrapie Plan for Great Britain was launched in 2001 and uptake has been widespread throughout the purebreeding sector of the sheep industry, with membership peaking at over 12 000 flocks in 2006. A total of 700 000 rams from 90 breeds have been genotyped. A comparison of ram lambs born in 2002 with those in 2006 shows evident changes in PrP genotype frequencies which are predicted to be associated with a reduction in disease risk. Various concerns have been raised regarding possible unintended consequences of widespread selection on PrP genotype, including impacts on other performance traits and possible effects on inbreeding and genetic diversity. To date, these concerns appear to be unfounded, as no consistent associations have been found with performance traits, nor are there likely to be any detectable impacts on inbreeding in mainstream breeds. Currently, semen banks have been implemented in Great Britain to store samples from animals of all common PrP genotypes, should these genotypes be required in the future. Various strategies to minimise future disease risks are discussed in the paper. 相似文献
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Kurosaki Y Ishiguro N Horiuchi M Shinagawa M 《The Journal of veterinary medical science / the Japanese Society of Veterinary Science》2005,67(3):321-323
Polymorphism of the PrP gene is a primary factor influencing susceptibility and incubation period in natural and experimental scrapie in sheep and goats. Polymorphisms of the caprine PrP gene in Japan were examined in 118 goats. Eight allelic variants and 19 genotypes were obtained. Amino acid polymorphisms were observed at 7 codons: 102, 142, 143, 240, 127, 146 and 211 (the latter 3 are novel polymorphisms). The polymorphisms at codons 142M and 143R, which are associated with the resistance to scrapie, were relatively rare in the present study. Thus, the present results provide information about the caprine PrP gene that may be useful for assessing the risk of goat scrapie. 相似文献
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朊病毒(PrPSc)是由动物体内正常朊蛋白PrPc构象改变形成的,PrPSc与PrPC在氨基酸序列上完全一致,PrPC中α-螺旋丰富而PrPSc富含β-折叠。目前,科学家还未研究清楚PrP的生理机能。人们普遍认为:人和动物感染朊病毒病时除PrP外还存在一些重要的辅助因子影响着PrPC变构、PrPSc传播、PrPSc引起神经细胞凋亡等病变过程,因此,研究朊蛋白的各种辅助因子将有助于阐明这方面的问题,这些辅助因子包括各种金属离子,如Ca2+、Cu2+、Fe2+、Mn2+。作者概述金属离子对朊蛋白结构和功能的影响,以及它们在朊病毒病的发病过程中可能起的作用。 相似文献
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