Article

The state of the prion

MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Nature Reviews Microbiology (Impact Factor: 23.32). 12/2004; 2(11):861-71. DOI: 10.1038/nrmicro1025
Source: PubMed

ABSTRACT There is little doubt that the main component of the transmissible agent of spongiform encephalopathies - the prion - is a conformational variant of the ubiquitous host protein PrP(C), and that the differing properties of various prion strains are associated with different abnormal conformations of this protein. The precise structure of the prion is not yet known, nor are the mechanisms of infection, conformational conversion and pathogenesis understood.

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Available from: Charles Weissmann, Mar 31, 2015
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    • "Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans, scrapie in sheep, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle (Aguzzi and Polymenidou, 2004; Caughey et al., 2009; Cobb and Surewicz, 2009; Collinge, 2001; Prusiner, 1998; Weissmann, 2004). The prion hypothesis asserts that the transmission of TSEs does not require nucleic acids, and that the infectious TSE agent is proteinaceous in nature, consisting of a misfolded form of prion protein (PrP) (Prusiner, 1982). "
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    ABSTRACT: Prion diseases, or transmissible spongiform encephalopathies (TSEs), are associated with the conformational conversion of the cellular prion protein, PrP(C), into a protease-resistant form, PrP(Sc). Here, we show that mutation-induced thermodynamic stabilization of the folded, α-helical domain of PrP(C) has a dramatic inhibitory effect on the conformational conversion of prion protein in vitro, as well as on the propagation of TSE disease in vivo. Transgenic mice expressing a human prion protein variant with increased thermodynamic stability were found to be much more resistant to infection with the TSE agent than those expressing wild-type human prion protein, in both the primary passage and three subsequent subpassages. These findings not only provide a line of evidence in support of the protein-only model of TSEs but also yield insight into the molecular nature of the PrP(C)→PrP(Sc) conformational transition, and they suggest an approach to the treatment of prion diseases.
    Cell Reports 07/2013; DOI:10.1016/j.celrep.2013.06.030 · 7.21 Impact Factor
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    • "Expression of this normal cell protein is essential to TSE pathogenesis. In contact with PrPd, PrPc undergoes a conformational change leading to pathogenic conversion (Weissmann 2004). "
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    ABSTRACT: Recent studies have established the involvement of nasal-associated lymphoid tissues, mainly the pharyngeal tonsil, in prion pathogenesis. However, the mechanisms of the associated neuroinvasion are still debated. To determine potential sites for prion neuroinvasion inside the ovine pharyngeal tonsil, the topography of heavy (200 kDa) and light (70 kDa) neurofilaments and of glial fibrillar acidic protein has been semi-quantitatively analysed inside the various compartments of the tonsil. The results show that the most innervated areas are the interfollicular area and the connective tissue located beneath the respiratory epithelium. The existence of rare synapses between follicular dendritic cells and nerve fibres inside the germinal centre indicates that this mechanism of neuroinvasion is possible but, since germinal centres of lymphoid follicles are poorly innervated, other routes of neuroinvasion are likely. The host PRNP genotype does not influence the pattern of innervation in these various tonsil compartments, unlike ageing during which an increase of nerve endings occurs in a zone of high trafficking cells beneath the respiratory epithelium. A minimal age-related increase of innervation inside the lymphoid follicles has also been observed. An increase in nerve fibre density around the lymphoid follicles, in an area rich in mobile cells such as macrophages and dendritic cells capable of capturing and conveying pathogen prion protein (PrPd), might ensure more efficient infectivity, not in the early phase but in the advanced phase of lymphoinvasion after the amplification of PrPd; alternatively, this area might even act as a direct site of entry during neuroinvasion.
    Cell and Tissue Research 03/2012; 348(1):167-76. DOI:10.1007/s00441-012-1376-x · 3.33 Impact Factor
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    • "hallmark is the accumulation, mostly in the extra-cellular space, of scrapie prion protein (PrP Sc ), an abnormal, partially protease-resistant isoform of the host-encoded cellular prion protein (PrP C ). PrP C is a membrane glycophosphatidylinositol (GPI)-anchored glycoprotein of 253 amino acids in humans that is highly preserved among species (Weissmann 2004). Post-translational modifications of the protein, such as its N-terminal truncation, may vary between mammalian species (Laffont-Proust et al. 2005, 2006). "
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    ABSTRACT: Prions, the agents responsible for transmissible spongiform encephalopathies, are infectious proteins consisting primarily of scrapie prion protein (PrP(Sc)), a misfolded, β-sheet enriched and aggregated form of the host-encoded cellular prion protein (PrP(C)). Their propagation is based on an autocatalytic PrP conversion process. Despite the lack of a nucleic acid genome, different prion strains have been isolated from animal diseases. Increasing evidence supports the view that strain-specific properties may be enciphered within conformational variations of PrP(Sc). In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most frequent form of prion diseases and has demonstrated a wide phenotypic and molecular spectrum. In contrast, variant Creutzfeldt-Jakob disease (vCJD), which results from oral exposure to the agent of bovine spongiform encephalopathy, is a highly stereotyped disease, that, until now, has only occurred in patients who are methionine homozygous at codon 129 of the PrP gene. Recent research has provided consistent evidence of strain diversity in sCJD and also, unexpectedly enough, in vCJD. Here, we discuss the puzzling biochemical/pathological diversity of human prion disorders and the relationship of that diversity to the biological properties of the agent as demonstrated by strain typing in experimental models.
    Journal of Neurochemistry 07/2011; 119(2):251-61. DOI:10.1111/j.1471-4159.2011.07399.x · 4.24 Impact Factor
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