Advances in research on Shadoo,shadow of prion protein

Prion plays a central role in the pathogenesis of transmissible spongiform encephalopathies, also known as prion diseases. However, the biology of the protein and the pathophysiology of these diseases remain largely unknown. It has been speculated that additional factor or factors may be involved in the pathogenesis of prion diseases. Recently, a PrP-like protein, recognized as shadow of prion protein （Shadoo, Sho）, is thought to be an interesting candidate factor because both the prion protein and Sho have been shown to have overlapping expression patterns and shared functions. Therefore, extensive study of Sho may advance our understanding of the enigmatical biology of prion and prion diseases. In this review, recent studies on Sho asso- ciated with prion diseases and functions are summarized. These studies have demonstrated the functional importance of Sho, and they further need to investigate its biological roles in prion diseases.     

Prion: the chameleon protein

From Creutzfeldt-Jakob disease (CJD) to variant CJD through Gerstmann-Str?ussler-Scheinker syndrome, kuru and fatal familial insomnia, the journey leading to current understanding of the basic aspects of human prion diseases has been full of unexpected, but often dramatic and always fascinating twists. Recent progress in modeling prion diseases and characterization of the various prion protein forms reveal that such a wide spectrum of the diseases is associated with the chameleon-like conformational features of prions.     

朊蛋白（PrP）与叠朊（Doppel）蛋白相关性的研究进展

近几年研究发现,与传染性海绵状脑病（TSE）发生密切相关的朊蛋白基因Prn,包括三种基因：Prnp（PrP编码基因）,Prnd（Doppel的编码基因）及Prnt．其中Prnd与Prnp关系更加密切．研究指出,二者的编码蛋白Doppel与PiP。的同源性虽然不高,但其翻译后修饰及空间结构却十分相似．这种相似性造成了二者在功能上的相关．如PrPc的缺失可能引起Doppel过表达;而prpc也似乎能够拮抗Doppel引起的神经毒性．     

Influence of PrP 106―126 on expression of laminin and fibronectin in astrocyte

Astrogliosis is a hallmark of prion disease, but the metabolic alterations of astrocytes remain poorly documented. A synthetic peptide corresponding to amino acid 106-126 of the human prion protein （PrP） has been shown to be toxic to neurons. In this study, the effects of PrP 106-126 on astrocytes were investigated in vitro. The proliferation of astrocytes was significantly （P 〈 0.05） increased when grown in media conditioned with PrP 106-126 （80 μmol/L） from microglia. The expression of laminin （LN） and fibronectin （FN） was examined at both mRNA and protein levels. The results showed that exposure of astrocytes to PrP 106-126 enhanced the expression of LN and FN. The increase of FN in astrocyte cultures required cytokines previously released by activated microglia. This study reveals the expression of LN and FN affected by PrP106-126.     

Scavenger, transducer, RNA chaperone? What ligands of the prion protein teach us about its function

Prion protein, a misfolded isoform of which is the essential component of the agent of prion diseases, still remains an enigmatic protein whose physiological functions are at best hypothetical. To gain a better insight into its putative role, many studies were undertaken to look for molecules that bind prion protein, and have notably identified divalent metal ions, several proteins, and nucleic acids. At first sight, the diversity of prion protein’s ligands seems of little help to infer a plausible function. However, the intrinsically disordered property of its N-terminal tail and the potential of the protein to adopt a transmembrane topology, can both be taken into account to predict its different states during its cellular cycle and its possible functions, of which the most promising correspond to a general scavenger, a sensor or adaptor in a signaling cascade, and an RNA chaperone. Received 16 August 2006; received after revision 7 November 2006; accepted 13 December 2006     

Tracking prions: the neurografting approach

The physical nature of the agent that causes transmissible spongiform encephalopathies (the 'prion'), is the subject of passionate controversy. Investigation of it has benefited tremendously from the use of transgenic and knockout technologies. However, prion diseases present several other enigmas, including the mechanism of brain damage and how the affinity of the agent for the central nervous system is controlled. Here we show that such questions can be effectively addressed in transgenic and knockout systems, and that pathogenesis may be clarified even before we can be certain about the nature of the infectious agent. Availability of mice overexpressing the Prnp gene (which encodes the normal prion protein) and Prnp knockout mice allows for selective reconstitution experiments aimed at expressing PrP in specific portions of the brain or in selected populations of hemato- and lymphopoietic origin. We summarize how such studies can offer insights into how prions administered to peripheral sites can gain access to central nervous tissue, and into the molecular requirements for spongiform brain damage.     

抗朊病毒药物筛选模型的研究进展

通过抗朊病毒药物筛选模型来筛选治疗以疯牛病为代表的朊病毒疾病的药物是目前国际上研究热点.结合作者正在进行的抗朊病毒药物筛选的研究,主要介绍了国际上流行的几种抗朊病毒药物筛选模型的原理与方法以及研究最新进展.     

Aptamers against prion proteins and prions

Prion diseases are fatal neurodegenerative and infectious disorders of humans and animals, characterized by structural transition of the host-encoded cellular prion protein (PrP^c) into the aberrantly folded pathologic isoform PrP^Sc. RNA, DNA or peptide aptamers are classes of molecules which can be selected from complex combinatorial libraries for high affinity and specific binding to prion proteins and which might therefore be useful in diagnosis and therapy of prion diseases. Nucleic acid aptamers, which can be chemically synthesized, stabilized and immobilized, appear more suitable for diagnostic purposes, allowing use of PrP^Sc as selection target. Peptide aptamers facilitate appropriate intracellular expression, targeting and re-routing without losing their binding properties to PrP, a requirement for potential therapeutic gene transfer experiments in vivo. Elucidation of structural properties of peptide aptamers might be used as basis for rational drug design, providing another attractive application of peptide aptamers in the search for effective anti-prion strategies.     

Accessibility of a critical prion protein region involved in strain recognition and its implications for the early detection of prions

Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated PrP27 – 30 detectable by the 3F4 antibody against human PrP109 – 112. We recently identified a new PK-resistant PrP species, designated PrP^*20, in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97 – 108 but not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP^*20 molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic mutant PrP accumulate not only PrP^*20 but also a small amount of 3F4-detected PK-resistant PrP27 – 30. Remarkably, during the course of human prion disease, a transition from an increase in 1E4-detected PrP^*20 to the occurrence of the 3F4-detected PrP27 – 30 was observed. Our study suggests that an increase in the level of PrP^*20 characterizes the early stages of prion diseases. Received 17 October 2007; received after revision 5 December 2007; accepted 14 December 2007     

Structural features of prions explored by sequence analysis. II. A PrP<Superscript>Sc</Superscript> model

Prion diseases are neurodegenerative disorders associated with a conformational conversion of the prion PrP protein, in which the β-strand content increases and that of the α helix decreases. However, the structure of the pathogenous form PrP^Sc, occurring after conformational conversion of the normal cellular form PrP^C, is not yet known. From sequence analysis, we have previously proposed that helix H2 of the prion PrP^C structure might be a key region for this structural conversion. More recently, we identified the TATA box-binding protein fold as a putative scaffold that may locally satisfy the predicted secondary-structure organisation of PrP^Sc. In the present analysis, we detail the schematic construction of PrP^Sc monomeric and dimeric models, based on this hypothesis. These models are globally compatible with available data and therefore may provide further insights into the structurally and functionally elusive PrP protein. Some comments are also devoted to a comparison of the yeast Ure2p prion and animal prions. Received 29 July 2002; received after revision 24 October 2002; accepted 24 October 2002 RID="*" ID="*"Corresponding author.