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UK Strategy for Research and Development on Human and Animal Health Aspects of Transmissible Spongiform Encephalopathies 2005-2008 snip... v6.1 Preface Since the announcement in 1996 of a possible link between BSE in cattle and vCJD in humans two strategy documents for research and development into transmissible spongiform encephalopathies (TSEs) have been produced by the UK government. TSE research has advanced significantly during the past few years, and as senior representatives of the UK public funders of TSE research, we considered it timely to review the current understanding of these diseases and set out a new research strategy that reflected the changes in knowledge. This document represents the first UK joint human and animal health strategy for TSE research and addresses issues that affect livestock, the food chain and public health. It highlights the improved co-ordination that has taken place between government departments since the publication of the Phillips Report and reflects the overlapping issues of relevance to both human and animal health. In the production of this document, we have drawn on a wide range of advice from all of the UK’s major funders of TSE research and from members of specialist advisory committees such as SEAC, which are detailed within. We have also undertaken wide consultation in the UK and overseas in an attempt to ensure the accuracy of the information included. We are particularly indebted to Professor Chris Bostock (formerly director of the Institute for Animal Health) for his 2004 review of the science, which forms the backbone of this document. With numbers of BSE cases continuing to fall and vCJD cases apparently stabilising in the UK, it would be easy to be complacent. However, the increasing incidence of chronic wasting disease in the USA reinforces the concern that TSEs are an international problem and one that will need to be monitored carefully for a number of years. In the UK, there remain key issues that continue to pose threats to animal and human health. Not least is the possibility of a non-symptomatic carrier state or the emergence of BSE-like illness in another species such as sheep. While every attempt is made to reduce exposure to disease it is not always possible to eradicate it completely. Disease management is thus often based on risk assessments of potential exposure and these are based on the latest scientific results. This document aims to highlight the major scientific uncertainties relating to TSEs and how these will be addressed by the research and development strategies of the major UK funders. The necessary experience of managing BSE and producing scientific evidence upon which to base control policies has led to the development of an extensive UK research base in human and animal health aspects of TSEs. The UK has a special responsibility to share its expertise in TSEs with Europe and the rest of the world to minimise the effects of TSE infection in other countries. Although considerable progress has been made, further studies are required to fill in the many gaps in our basic understanding of TSEs and in our knowledge of how TSE epidemics can be effectively controlled. It is therefore vital that the UK research base is maintained and that a co-ordinated and effective funding strategy is adopted for new research. Science develops and inevitably this strategy will require regular reassessment. 3v6.1 Professor Sir John Pattison Director of Research Department of Health Dr John Bell Chief Executive Food Standards Agency Professor Colin Blakemore FRS Chief Executive Medical Research Council Professor Julia Goodfellow CBE Chief Executive Biotechnology and Biological Sciences Research Council Professor Howard Dalton FRS Chief Scientific Adviser Department for Environment, Food and Rural Affairs 4v6.1 Executive Summary 5v6.1 6v6.1 Introduction snip... 2.15.3.2 It is difficult to ensure that all cases of vCJD are correctly diagnosed and reported and there is always the worry that some could be missed. Variant CJD occurs in a much younger age group than sporadic CJD68 and it is a concern that cases are perhaps being missed in children and older adults. A survey of over 1,000 children with progressive intellectual and neurological deterioration (PIND), a group that would include vCJD patients, found only previously reported cases of vCJD, indicating that vCJD in children is not being missed68, 314. Although vCJD has been diagnosed in a 74 year old patient315, the possibility remains that cases of vCJD are being missed amongst the elderly. One attempt to estimate the prevalence of infection, as opposed to the incidence of clinical vCJD, is based on a search for the characteristic presence of PrPSc in infected lymphoid tissue in archived specimens of tonsils and appendices removed from patients aged 10 to 50 between 1995 and 1999. The interim findings of this study reported one PrPSc-positive appendix amongst 8318 samples examined, which gives an estimated detectable prevalence of PrPSc accumulation in 120 per million of the population316. However, the finding of a further two PrPSc-positive samples, giving a total of three positive samples in 12 674 samples examined, confirm the wisdom of screening the larger number of samples being collected as part of the National Tonsil Archive333. snip... 2.2 The prion and other hypotheses 2.2.1 An animal with a TSE infection commonly exhibits an abnormal form (PrPSc or prion) of the cellular prion protein (PrPC). Deposits of PrPSc can take many forms ranging from diffuse widespread distribution to local concentrations of highly ordered aggregates, called amyloid plaques. Deposits of PrPSc can be identified under the microscope in sections of body tissue by selective staining and can be separated from PrPC because PrPSc is insoluble and relatively resistant to protease enzymes used to digest proteins. 2.2.2 The correlation between TSE infection and PrPSc led to the prion hypothesis, that the abnormal form of prion protein is the infectious agent8, 9, 10. Although accepted by many in 19v6.1 the field today, it was highly contentious at first because it went against the then-accepted view that all inherited biological information must be encoded in nucleic acid, DNA or RNA. Alternative hypotheses for the infectious agent include a conventional virus of unknown type11 or a "virino"- an informational molecule, expected to be a small piece of nucleic acid, which is not encoded in the host and which codes for its own replication and binds to the prion protein12. 2.2.3 To date neither a virus nor a virino nucleic acid has been found and most research has focussed on the PrP molecule. Although progress has been made in understanding the structure, function and role in disease of various forms of PrP, the molecular basis of its suggested infectiousness and how it is propagated have not been described. Nor has normal PrP been converted into an infectious form in a test tube in a laboratory, which would provide a formal proof of the hypothesis. snip... 2.5.4 Many strains of TSEs, even those that have been biologically cloned by repeated passage within a species, can change their characteristics when transmitted from one species to another. This is perhaps not surprising, if the prion hypothesis is correct, given that different species have PrPCs with different amino acid sequences. BSE has been transmitted to a number of different species either "naturally", through contaminated food, as with cats, exotic ruminants, and humans, or experimentally, through injection or feeding, for example sheep, goats and pigs. Each of these species has a different PrPC, but where it has been tested, the strain characteristics of their BSE-derived TSEs are the same as for BSE from cattle. This "stability" of the BSE strain in different PrP backgrounds challenges the notion that shape of PrP in PrPSc encodes the properties of a strain. The shape that, according to the prion hypothesis, defines the BSE strain must be independent of differences, often large, between the amino acid sequence in PrPC. Alternatively, there may be one or more other molecules (yet to be identified) that associate with PrP to determine the strain properties. Knowing the molecular basis of TSE strains is, therefore, at the heart of understanding the nature of the TSE agent. snip... 3.3.2.4 The prion protein has not been unequivocally shown to be the infectious agent of TSE disease. Although some work is investigating the correlation between PrPSc and infectivity, using transgenic mouse models, this remains a fundamental gap in knowledge. The unequivocal identification of the TSE agent would have a profound effect on the development of appropriate diagnostic tests. For this reason, the search for a non-PrPSc marker for disease is important. Some work is ongoing in the search for alternative markers, using approaches such as metabolomics and proteomics. These approaches search for consistent differences between control and infected animals at several stages of the incubation period. However, an alternative marker for the detection of the disease has not yet been identified. Further characterisation of different conformers of PrP after digestion with proteases and the development and application of other conformation-dependent techniques for detecting PrPSc may allow a better understanding of the significance of atypical results observed in large-scale surveillance studies. snip... 3.3.3 Prospects for treatment 3.3.3.1 Current strategies involve screening large pharmaceutical libraries to identify possible therapeutic compounds. However, a better understanding of the structures of prion proteins and their biology could lead to a more targeted approach, allowing the design of small molecules which could block abnormal prion protein formation. Approaches underpinning the development of therapeutics remain a priority for the research councils. The identification of a natural mechanism for clearing infectivity from the body could also be exploited for therapeutic purposes. 3.3.3.2 It seems unlikely that a treatment will become available soon to repair damage to the CNS. The research councils fund work on the generic development of stem cell therapy. However, therapies that seek to repair damaged tissue are far in the future and even then would only be of value once infection had been halted. While several strategies to develop a therapeutic are aimed at inhibiting PrPC to PrPSc conversion, success is likely to be improved by the development of good diagnostics to identify individuals with pre-clinical infection. 3.3.3.3 The development and evaluation of a potential therapy is a detailed process that usually takes many years. In addition to continued support for such work, DH and MRC are establishing the infrastructure for rapid clinical evaluation of any agents that have demonstrated anti-prion activity in animals or in vitro. To this end a clinical trial protocol has been developed in conjunction with families and carers through the Medical Research Council's Prion Unit and Clinical Trials Unit, and building capacity for undertaking such work remains a priority. 53 snip... 3.4.0.7 The possibility of an infectious carrier state in apparently healthy animals and humans highlights our limited knowledge of TSE diseases. Work on TSEs may also produce results that have significance for the understanding of other groups of diseases 54v6.1 such as the neurodegenerative changes involved in Alzheimer’s and other amyloid brain diseases. A full understanding of TSE transmission is likely to require advances in the understanding of the immune system and will provide insights into aspects of human and animal genetic variability. The Research Councils (BBSRC and MRC) support this underpinning biomedical science. snip... 3.4.2 The MRC has identified the following key areas in which it would like to continue to receive innovative research proposals: * Council has approved programmes of work within these areas at the MRC Prion Unit 55 http://www.mrc.ac.uk/pdf-about-tse_uk_strategy_june2005.pdf Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease Summary ratio of protease-resistant prion protein (PrPSc), and type 2 PrPSc display unglycosylated core fragments of acids 82 and 97, respectively. Methods We generated anti-PrP monoclonal antibodies to K cleavage sites. These antibodies, which were Findings We studied 114 brain samples from 70 patients Every patient classified as CJD type 2, and all variant cerebellum and other PrPSc-rich brain areas, with a Interpretation The regular coexistence of multiple electrophoretic PrPSc mobilities as surrogates for classifications. into debate and introduce interesting questions about human CJD types. For example, do human prion types exist in a dynamic equilibrium in the brains of affected individuals? Do they coexist in most or even all CJD cases? Is the biochemically identified PrPSc type simply the dominant type, and not the only PrPSc species? http://neurology.thelancet.com Creutzfeldt-Jakob Disease Helen M. Yull,* Diane L. Ritchie,* Jan P.M. Langeveld,? Fred G. van Zijderveld,? Moira E. Bruce,? James W. Ironside,* and Mark W. Head* From the National CJD Surveillance Unit,* School of and Clinical Medicine, University of Edinburgh, Edinburgh, United Kingdom; Central Institute for Animal Disease (CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt- Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain. (Am J Pathol 2006, 168:151-157; DOI: 10.2353/ajpath.2006.050766) snip... Discussion In the apparent absence of a foreign nucleic acid genome associated with the agents responsible for transmissible spongiform encephalopathies or prion diseases, efforts to provide a molecular definition of agent strain have focused on biochemical differences in the abnormal, disease-associated form of the prion protein, termed PrPSc. Differences in PrPSc conformation and glycosylation have been proposed to underlie disease phenotype and form the biochemical basis of agent strain. This proposal has found support in the observation that the major phenotypic subtypes of sCJD appear to correlate with the presence of either type 1 or type 2 PrPSc in combination with the presence of either methionine or valine at codon 129 of the prion protein gene.2 Similarly, the PrPSc type associated with vCJD correlates with the presence of type 2 PrPSc and is distinct from that found in sCJD because of a characteristically high occupancy of both N-linked glycosylation sites (type 2B).6,11 The means by which such conformational difference is detected is somewhat indirect; relying on the action of proteases, primarily proteinase K, to degrade the normal Figure 6. Type 1 PrPSc is a stable minority component brain. Western blot analysis of PrP in a sample of of vCJD during digestion with proteinase K is shown. are indicated in minutes (T0, 5, 10, 30, 60, 120, 180). probed with 3F4, which detects both type 1 and type 2 which detects type 1. The insert shows a shorter course study from a separate experiment also probed included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Figure 7. A minority type 1-like PrPSc is found in vCJD to mice and in BSE. Western blot analysis of PrPSc in a sample of tonsil from a case of vCJD (Tonsil), in a of a wild-type mouse (C57BL) infected with vCJD and in BSE brain (BSE) is shown. Tissue extracts were digested Duplicate blots were probed with either 3F4 or 6H4, type 1 and type 2 PrPSc, and with 12B2, which detects included samples of cerebral cortex from a case of 1) and molecular weight markers (Markers) indicate Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155 AJP January 2006, Vol. 168, No. 1 cellular form of PrP and produce a protease-resistant core fragment of PrPSc that differs in the extent of its N-terminal truncation according to the original conformation. A complication has recently arisen with the finding that both type 1 and type 2 can co-exist in the brains of patients with sCJD.2,5-8 More recently this same phenomenon has been demonstrated in patients with iatrogenically acquired and familial forms of human prion disease. 9,10 The existence of this phenomenon is now beyond doubt but its prevalence and its biological remain a matter of debate. Conventional Western blot analysis using antibodies that detect type 1 and type 2 PrPSc has severe quantitative limitations for the co-detection of type 1 and type 2 PrPSc in individual samples, suggesting that the prevalence of co-occurrence of the two types might be underestimated. We have sought to circumvent this problem by using an antibody that is type 1-specific and applied this to the sole remaining human prion disease where the phenomenon of mixed PrPSc types has not yet been shown, namely vCJD. These results show that even in vCJD where susceptible individuals have been infected supposedly by a single strain of agent, both PrPSc types co-exist: a reminiscent of that seen when similarly discriminant antibodies were used to analyze experimental BSE in sheep.14,17 In sporadic and familial CJD, individual brains can show a wide range of relative amounts of the two types in samples from different regions, but where brains have been thoroughly investigated a predominant type is usually evident.2,6,10 This differs from this on vCJD, where type 1 is present in all samples but always as a minor component that never reaches a level at which it is detectable without a type 1-specific antibody. It would appear that the relative between type 1 and type 2 is controlled within certain limits in the vCJD brain. A minority type-1-like band is also detected by 12B2 in vCJD tonsil, in BSE brain and in the brains of mice experimentally infected with vCJD, suggesting that this balance of types is agent, rather than host or tissue, specific. Interestingly the signature" of the type 2 PrPSc found in vCJD (type 2B) is also seen in the type 1 PrPSc components, suggesting that it could legitimately be termed type 1B. PrPSc isotype analysis has proven to be extremely useful in the differential diagnosis of CJD and is continue to have a major role in the investigation of human prion diseases. However, it is clear, on the basis of these findings, that molecular typing has quantitative and that any mechanistic explanation of prion replication and the molecular basis of agent strain must accommodate the co-existence of multiple prion protein conformers. Whether or not the different conformers we describe here correlate in a simple and direct way with agent strain remains to be determined. In principle two interpretations present themselves: either the two conformers can be produced by a single strain of agent or vCJD (and, therefore, presumably BSE) results from a mixture of strains, one of which generally Evidence for the isolation in mice of more than one strain from individual isolates of BSE has been presented previously.18,19 One practical consequence of our findings is that the correct interpretation of transmission studies will depend on a full examination of the balance of molecular types present in the inoculum used to transmit disease, in to a thorough analysis of the molecular types that arise in the recipients. Another consequence relates to the diagnostic certainty of relying on PrPSc molecular type alone when considering the possibility of BSE or secondary transmission in humans who have a genotype other than methionine at codon 129 of the PRNP gene. In this context it is interesting to note minority type 1B component resembles the type 5 PrPSc described previously to characterize vCJD transmission into certain humanized PRNP129VV transgenic mouse models.12,20 This apparently abrupt change in molecular phenotype might represent a selection process imposed by this particular transgenic mouse model. Irrespective of whether this proves to be the case, the results shown here point to further complexities in the relationship the physico-chemical properties of the prion protein, human disease phenotype, and prion agent strain. Acknowledgments snip... Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157 AJP January 2006, Vol. 168, No. 1 ...TSS (2005), 31 , 565-579 doi: 10.1111/j.1365-2990.2005.00697.x © 2005 Blackwell Publishing Ltd 565 Blackwell Science, LtdOxford, UKNANNeuropathology and 316565579 Review article Phenotypic variability in human prion diseases J. W. Ironside, D. L. Ritchie and M. W. Head National Creutzfeldt-Jakob Disease Surveillance Unit, J. W. Ironside, D. L. Ritchie and M. W. Head (2005) Neuropathology and Applied Neurobiology 31, 565-579 Phenotypic variability in human prion diseases Human prion diseases are rare neurodegenerative disorders that can occur as sporadic, familial or acquired disorders. Within each of these categories there is a wide range of phenotypic variation that is not encountered in other neurodegenerative disorders. The identification of the prion protein and its key role in the pathogenesis of this diverse group of diseases has allowed a fuller of factors that influence disease phenotype. In particular, the naturally occurring polymorphism at codon 129 in the prion protein gene has a major influence on the phenotype in sporadic, familial and acquired prion diseases, although the underlying mechanisms remain unclear. Recent technical advances have improved our ability to study the isoforms of the abnormal prion protein in the brain and in other tissues. This has lead to the of molecular strain typing, in which different isoforms of the prion protein are proposed to correspond to individual strains of the transmissible agent, each with specific biological properties. In sporadic disease there are at least six major combinations of codon 129 genotype and prion protein isotype, which appear to relate to distinctive clinical subgroups of this disease. However, these relationships are proving to be more complex than first considered, particularly in cases with more than a single prion protein isotype in the brain. Further work is required to clarify these relationships and to explain the mechanism of neuropathological targeting of specific brain regions, which accounts for the diversity of clinical features within human prion diseases. © 2005 Blackwell Publishing Ltd, Neuropathology and sporadic CJD-like prion strains in transgenic mice expressing human prion protein The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002 Emmanuel A.Asante, Jacqueline M.Linehan, Melanie Desbruslais, Susan Joiner, Ian Gowland, Andrew L.Wood, Julie Welch, Andrew F.Hill, Sarah E.Lloyd, Jonathan D.F.Wadsworth and John Collinge1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.uk Variant Creutzfeldt±Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSEderived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure. snip... These studies further strengthen the evidence that vCJD is caused by a BSE-like prion strain. Also, remarkably, the key neuropathological hallmark of vCJD, the presence of abundant ¯orid PrP plaques, can be recapitulated on BSE or vCJD transmission to these mice. However, the most surprising aspect of the studies was the ®nding that an alternate pattern of disease can be induced in 129MM Tg35 mice from primary transmission of BSE, with a molecular phenotype indistinguishable from that of a of sporadic CJD. This ®nding has important potential implications as it raises the possibility that some humans infected with BSE prions may develop a clinical disease indistinguishable from classical CJD associated with type 2 PrPSc. This is, in our experience, the commonest molecular sub-type of sporadic CJD. In this regard, it is of interest that the reported incidence of sporadic CJD has risen UK since the 1970s (Cousens et al., 1997). This has been attributed to improved case ascertainment, particularly as much of the rise is reported from elderly patients and similar rises in incidence were noted in other European countries without reported BSE (Will et al., 1998). However, it is now clear that BSE is present in many European countries, albeit at a much lower incidence than was seen in the UK. While improved ascertainment is likely to be a major factor in this rise, that some of additional cases may be related to BSE exposure cannot be ruled out. It is of interest in this regard that a 2-fold increase in the reported incidence of sporadic CJD in 2001 has recently been reported for Switzerland, a country that had the highest incidence of cattle BSE in continental Europe between 1990 and 2002 (Glatzel et al., 2002). No epidemiological case±control studies with strati®cation of CJD cases by molecular sub-type have yet been reported. It will be important to review the incidence of sporadic CJD associated with PrPSc type 2 and other molecular in both BSE-affected and unaffected countries in the light of these ®ndings. If human BSE prion infection can result in propagation of type 2 PrPSc, it would be expected that such cases would be indistinguishable on clinical, pathological and molecular criteria from classical CJD. It may also be expected that such prions would behave biologically like those isolated from humans with sporadic CJD with type 2 PrPSc. The transmission properties of prions associated with type 2 PrPSc from BSE-inoculated 129MM Tg35 mice are being investigated by serial passage. We consider these data inconsistent with contamination of some of the 129MM Tg35 mice with sporadic CJD prions. These transmission studies were performed according to rigorous biosafety protocols for preparation of inocula and both the inoculation and care of mice, which are all uniquely identi®ed by sub-cutaneous transponders. However, crucially, the same BSE inocula have been used on 129VV Tg152 and 129MM Tg45 mice, which are highly sensitive to sporadic CJD but in which such transmissions producing type 2 PrPSc were not observed. Furthermore, in an independent experiment, separate inbred lines of wild-type mice, which are highly resistant to sporadic CJD prions, also propagated two distinctive PrPSc types on challenge with either BSE or vCJD. No evidence of spontaneous prion disease or PrPSc has been seen in groups of uninoculated or mock-inoculated aged 129MM Tg35 mice. While distinctive prion isolates have been derived from BSE passage in mice previously (designated 301C and 301V), these, in contrast to the data presented here, are propagated in mice expressing different prion proteins (Bruce et al., 1994). It is unclear whether our ®ndings indicate the existence of more than one prion strain in individual cattle with BSE, with selection and preferential replication of distinct strains by different hosts, or that `mutation' of a unitary BSE strain occurs in some types of host. Western blot analysis of single BSE isolates has not shown evidence of the presence of a proportion of monoglycosylated dominant PrPSc type in addition to the diglycosylated dominant pattern (data not shown). Extensive strain typing of large numbers of individual BSE-infected cattle either by biological or molecular methods has not been reported. Presumably, the different genetic background of the different inbred mouse lines is crucial in determining which prion strain propagates on BSE inoculation. The transgenic mice described here have a mixed genetic background with contributions from FVB/N, C57BL/6 and 129Sv inbred lines; each mouse will therefore have a different genetic background. This may explain the differing response of individual 129MM Tg35 mice, and the difference between 129MM Tg35 and 129MM Tg45 mice, which are, like all transgenic lines, populations derived from single founders. Indeed, the consistent distinctive strain propagation in FVB and C57BL/6 versus SJL and RIIIS lines may allow mapping of genes relevant to strain selection and propagation, and these studies progress. That different prion strains can be consistently isolated in different inbred mouse lines challenged with BSE prions argues that other species exposed to BSE may develop prion diseases that are not recognizable as being caused by the BSE strain by either biological or molecular strain typing methods. As with 129MM Tg35 mice, the prions replicating in such transmissions may be from naturally occurring prion strains. It remains of considerable concern whether BSE has transmitted to, and is being maintained in, European sheep ¯ocks. Given the diversity of sheep breeds affected by scrapie, it has to be considered that some sheep might have become infected with BSE, but propagated a distinctive strain type indistinguishable from those of natural sheep scrapie. ... The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002 6358 ãEuropean Molecular Biology Organization http://embojournal.npgjournals.com/cgi/reprint/21/23/6358 J Neuropsychiatry Clin Neurosci 17:489-495, November 2005 This study characterizes the type and timing of CONCLUSIONS Historically, psychiatric manifestations have been http://neuro.psychiatryonline.org/cgi/content/abstract/17/4/489 Personal Communication -------- Original Message -------- Valine 129 Prevents Expression of Variant CJD Phenotype Jonathan D. F. Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner, Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,* Sebastian Brandner, John Collinge. Variant Creutzfeldt-Jakob disease (vCJD) is a unique clinicopathological and molecular phenotype of human associated with infection with bovine spongiform prions. Here, we found that generation of this required expression of human prion protein (PrP) with Expression of human PrP with valine 129 resulted in a remarkably, persistence of a barrier to transmission of subpassage. Polymorphic residue 129 of human PrP distinct prion strains after BSE prion infection. Thus, human infection with BSE-derived prions may result in novel phenotypes in addition to vCJD, depending on the source and the recipient. snip... 3 DECEMBER 2004 VOL 306 SCIENCE http://www.sciencemag.org derived from bovine spongiform encephalopathy transmissions to inbred mice Sarah E. Lloyd, Jacqueline M. Linehan, Melanie Desbruslais, Susan Joiner, Jennifer Buckell, Sebastian Brandner, Jonathan D. F. Wadsworth and John Collinge Correspondence John Collinge j.collinge@prion.ucl.ac.uk MRC Prion Unit and Department of Neurodegenerative University College, London WC1N 3BG, UK Received 9 December 2003 Accepted 27 April 2004 Distinct prion strains can be distinguished by and biochemical properties of disease-associated prion Reliable comparisons of mouse prion strain properties genetically identical mice, as host prion protein to modulate prion disease phenotypes. While multiple sheep scrapie and Creutzfeldt-Jakob disease, bovine thought to be caused by a single prion strain. Primary of inbred mice resulted in the propagation of two prion strains may have been isolated. To investigate subpassaged in a single line of inbred mice (SJL) and strains had been identified. MRC1 was characterized by a mono-glycosylated-dominant PrPSc type and a deposits, while MRC2 displayed a much longer incubation a di-glycosylated-dominant PrPSc type and a distinct and neuronal loss. These data indicate a crucial prion strain selection and propagation in mice. It is may also be possible in BSE prion infection in humans snip... Journal of General Virology (2004), 85, 2471-2478 DOI http://vir.sgmjournals.org/cgi/content/abstract/85/8/2471 Cristina Casalone *, Gianluigi Zanusso , Pierluigi *Centro di Referenza Nazionale per le Encefalopatie Edited by Stanley B. Prusiner, University of Transmissible spongiform encephalopathies (TSEs), or C.C. and G.Z. contributed equally to this work. ||To whom correspondence should be addressed. E-mail: salvatore.monaco@mail.univr.it . www.pnas.org/cgi/doi/10.1073/pnas.0305777101 snip... Phenotypic Similarities Between BASE and sCJD. The of CJD brains was initially demonstrated in primates classification of atypical cases as CJD was based on (28). To date, no systematic studies of strain typing been provided, and classification of different subtypes on clinical, neuropathological, and molecular features PRNP codon 129 and the PrPSc glycotype) (8, 9, 15, 19). The importance of molecular PrPSc characterization in the identity of TSE strains is underscored by several showing that the stability of given disease-specific maintained upon experimental propagation of sCJD, familial CJD, and vCJD isolates in transgenic PrP-humanized mice (8, 29). Similarly, biochemical properties of BSE- and PrPSc molecules remain stable after passage to mice expressing bovine PrP (30). Recently, however, it has been reported that PrP-humanized mice inoculated with BSE may also propagate a distinctive PrPSc type, with a dominant'' pattern and electrophoretic mobility of the unglycosylated fragment slower than that of vCJD and Strikingly, this PrPSc type shares its molecular a PrPSc molecule found in classical sCJD. This variance with the PrPSc type found in MV2 sCJD cases and in cattle BASE, showing a monoglycosylated-dominant faster electrophoretic mobility of the as compared with BSE. In addition to molecular properties of PrPSc, BASE and MV2 sCJD share a distinctive pattern of intracerebral PrP deposition, which occurs as amyloid-kuru plaques. Differences were, however, the regional distribution of PrPSc. While inMV2 sCJD largest amounts of PrPSc were detected in the cerebellum, brainstem, and striatum, in cattle BASE these areas involved and the highest levels of PrPSc were recovered thalamus and olfactory regions. In conclusion, decoding the biochemical PrPSc signature of individual human and animal TSE strains may allow the of potential risk factors for human disorders with unknown etiology, such as sCJD. However, although BASE and sCJD share several characteristics, caution is dictated a link between conditions affecting two different mammalian species, based on convergent biochemical properties of PrPSc types. Strains of TSE agents may be better characterized upon passage to transgenic mice. In the until this is accomplished, our present findings epidemiological surveillance of cattle TSE and sCJD molecular criteria. http://www.pnas.org/cgi/reprint/0305777101v1 Published online before print March 20, 2001, Neurobiology * Commissariat à l'Energie Atomique, Service de Edited by D. Carleton Gajdusek, Centre National de la snip... Characterization of the CJD and Scrapie Strains. The lesion profiles of sCJD and iCJD differed only snip... http://www.pnas.org/cgi/content/full/041490898v1 Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC. Kuru and Creutzfeldt-Jakob disease of humans and PMID: 6997404 NOTES Interspecies Transmission of Chronic Wasting Disease Squirrel Monkeys (Saimiri sciureus) Richard F. Marsh,1? Anthony E. Kincaid,2 Richard A. Department of Animal Health and Biomedical Sciences, Physical Therapy2 and Department of Medical Nebraska 68178; and Department of Veterinary Molecular State University, Bozeman, Montana 597183 Received 3 May 2005/Accepted 10 August 2005 Chronic wasting disease (CWD) is an emerging prion to humans following exposure to CWD-infected tissues is primates to CWD, two squirrel monkeys were inoculated CWD-inoculated squirrel monkeys developed a progressive 31 and 34 months postinfection. Brain tissue from the isoform of the prion protein, PrP-res, and displayed transmission of CWD to primates. snip... JOURNAL OF VIROLOGY, Nov. 2005, p. 13794-13796 Vol. 0022-538X/05/$08.00!0 Copyright © 2005, American Society for Microbiology. ============================================= http://www.neurology.org/cgi/eletters/60/2/176#535 LANCET INFECTIOUS DISEASE JOURNAL BMJ http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2 BMJ http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1
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