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(a) Vacuolar degeneration in the superior colliculus from a 651-day-old male IM mouse killed with clinical neurological disease 611 days post-injection. (b) Vacuolar degeneration in the spinal cord from a 510-day-old female IM mouse killed with clinical neurological disease 470 days post-injection. (c) Asymmetrical vacuolation in the right superior colliculus and right visual cortex from a 573-day-old female VM mouse killed with clinical neurological disease 524 days post-injection. (d) Amyloid plaques at the margin of the corpus caUosum and hippocampus from a 537-day-old female VM mouse killed with clinical neurological disease 507 days postinjection . Haematoxylin and eosin stain. Bar markers in (a), (b) and (d) represent 400 nm, in (c) 1330 nm.
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Transmission from four cases of bovine spongiform encephalopathy (BSE) to mice resulted in neurological disease in 100% of recipient animals, after incubation periods of between 265 and 700 days post-injection. The results from the four cases were very similar to one another. There were major differences in the incubation period between the four in...
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Context 1
... period, indicating close host control of the infective and replicative events leading to clinical illness. The neuropathology in the affected mice consisted of a characteristic vacuolar degeneration in areas of grey matter in brain and spinal cord (Fig. l a and b). Vacuolation in white matter tracts was inconspicuous. Asymmetrical vacuolation (Fig. 1 c) and amyloid plaques (Fig. l d) occurred in VM, IM (Table 2) and C57BL x VM mice (data not shown). The lesion profiles (Fig. 2) in BSE-infected mice differed between mouse strains, but within each strain there were few differences between the BSE cases. In VM and IM mice the lesion profiles of the scrapie transmission were broadly ...
Context 2
... a high dose (10 -1 dilution) the incubation periods following i.c. injection were 25 to 56 days longer for C57BL and 35 to 49 days longer for RIII mice than when i.c. and i.p. routes were combined (Tables 1 and 3). No differences in titre endpoints were found between the mouse strains, and a 62 to 93 day significant (P<0-01 to 0-001) difference in average incubation period between RIII and C57BL mice was retained throughout the dilution series. ...
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Citations
... We also found that the second Nlinked glycan (adjacent to the C-terminal domain) inhibits seeding by Mo protein-only recPrP Sc . While PrP C from both bank voles and G2 mutant mice are susceptible to conversion by recombinant protein-only protein seeds and other natural strains, both are relatively resistant to BSE-derived prions [17,35], which is surprising since BSE prions readily infect wildtype mice [51] and many other animal species. Taken together, these observations suggest that Mo G2 PrP C and BV PrP C may share a common folding mechanism to form PrP Sc , and that this mechanism may be able to accommodate a wide variety of PrP Sc conformations (except for BSE, which may propagate by a different folding mechanism). ...
Prions are unorthodox pathogens that cause fatal neurodegenerative diseases in humans and other mammals. Prion propagation occurs through the self-templating of the pathogenic conformer PrPSc, onto the cell-expressed conformer, PrPC. Here we study the conversion of PrPC to PrPSc using a recombinant mouse PrPSc conformer (mouse protein-only recPrPSc) as a unique tool that can convert bank vole but not mouse PrPC substrates in vitro. Thus, its templating ability is not dependent on sequence homology with the substrate. In the present study, we used chimeric bank vole/mouse PrPC substrates to systematically determine the domain that allows for conversion by Mo protein-only recPrPSc. Our results show that that either the presence of the bank vole amino acid residues E227 and S230 or the absence of the second N-linked glycan are sufficient to allow PrPC substrates to be converted by Mo protein-only recPrPSc and several native infectious prion strains. We propose that residues 227 and 230 and the second glycan are part of a C-terminal domain that acts as a linchpin for bank vole and mouse prion conversion.
... Strain isolation is usually obtained through the inoculation of scrapie-infected material from goat and sheep, BSE-derived material from cattle or human sources of PrP Sc from the brains of deceased subjects with sCJD or GSS [65,66,[75][76][77][78]. Usually, in order to obtain a stabilized strain, several passages of the same source in one species with a constant background are needed. Examples of mouse-adapted scrapie prion strains are RML, ME7, 139A and 79A, while mouse strains generated by the inoculation of BSE and sCJD prions are the 301C and Fukuoka, respectively [79][80][81]. Interestingly, the agent responsible for prion disorders seems to be able to infect some animal species and not others. This phenomenon, known as "species barrier" depends mainly on genetic variability and on sequence difference of PrP C in the host animal and explains the prolongation in the incubation period observed [82,83]. ...
Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: the presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-β (Aβ), tau, α-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions. These observations have led to the terminology of “prion-like” to distinguish between conditions with noninfectious characteristics but similarities with the prion replication and propagation process. Prions are considered to adapt their conformation to changes in the context of the environment of replication. This process is known as either prion selection or adaptation, where a distinct conformer present in the initial prion population with higher propensity to propagate in the new environment is able to prevail over the others during the replication process. In the last years, many studies have shown that prion-like proteins share not only the prion replication paradigm but also the specific ability to aggregate in different conformations, i.e., strains, with relevant clinical, diagnostic and therapeutic implications. This review focuses on the molecular basis of the strain phenomenon in prion and prion-like proteins.
... Overall, net increases and decreases appear more marked in the RML model; as this was only the second passage of BSE in these mice the length of the incubation period had a higher standard deviation. In addition, there is variation between these strains in the regions of the brain in which PrP res accumulation is most dense; scrapie strains are generally denser in all regions of the hippocampus whereas BSE PrP res is less abundant in the hippocampus apart from the CA2 region 10,11 . Similarities between sample groups include a net increase in expression of neuronal genes in the CA1 region of both models during the first half (preclinical) period of disease, and increased expression of glial-enriched genes towards the end of the incubation period. ...
Multiple cell types and complex connection networks are an intrinsic feature of brain tissue. In this study we used expression profiling of specific microscopic regions of heterogeneous tissue sections isolated by laser capture microdissection (LCM) to determine insights into the molecular basis of brain pathology in prion disease. Temporal profiles in two mouse models of prion disease, bovine spongiform encephalopathy (BSE) and a mouse-adapted strain of scrapie (RML) were performed in microdissected regions of the CA1 hippocampus and granular layer of the cerebellum which are both enriched in neuronal cell bodies. We noted that during clinical disease the number of activated microglia and astrocytes that occur in these areas are increased, thereby likely diluting the neuronal gene expression signature. We performed a comparative analysis with gene expression profiles determined from isolated populations of neurons, microglia and astrocytes to identify transcripts that are enriched in each of these cell types. Although the incubation periods of these two models are quite different, over 300 days for BSE and ~160 days for RML scrapie, these regional microdissections revealed broadly similar profiles. Microglial and astrocyte-enriched genes contributed a profound inflammatory profile consisting of inflammatory cytokines, genes related to phagocytosis, proteolysis and genes coding for extracellular matrix proteins. CA1 pyramidal neurons displayed a net upregulation of transcription factors and stress induced genes at pre-clinical stages of disease while all tissues showed profound decrease of overlapping genes related to neuronal function, in particular transcripts related to neuronal communication including glutamate receptors, phosphatase subunits and numerous synapse-related markers. Of note, we found a small number of genes expressed in neurons that were upregulated during clinical disease including, COX6A2, FZD9, RXRG and SOX11, that may be biomarkers of neurodegeneration.
... 2,3 TSEs strains can be defined on the basis of differences in the conformation, glycosylation ratio, protease resistance, and aggregation state of the core of PrP Sc . [4][5][6][7][8][9] In addition, mice inocu- lated with TSEs can serve as strain characteri- zation and provide reliable indicators for incubation periods and vacuolar degenerative patterns, referred to as lesion profiles [10][11][12] . Recently, rare atypical forms of BSE have been reported as active surveillance progressed. ...
M2B cells with persistent classical bovine spongiform encephalopathy (C-BSE) have been established previously. In this study, we performed strain characterization of the M2B cell line in bovine PrPC overexpressing mice (Tg 1896). Mice intracranially inoculated with M2B cells and C-BSE survived for 451 ± 7 and 465 ± 31 d post inoculation, respectively. Although biochemical properties, including deglycosylation and conformational stability, differed between M2B cells and C-BSE, inoculation with M2B cell lysate and C-BSE resulted in comparable phenotypes. Comparable vacuolation scores and PrPSc depositions were observed in the brain of Tg 1896 inoculated with both M2B cell lysate and C-BSE. Our results show that biochemical and biological characteristics of M2B cells and C-BSE are classifiable in the same strain.
... At that time no other TSE was known in cattle and studies to define the disease phenotype in this species were initiated. One of the most important parameters was to characterise the strain of the agent by defining the disease phenotype in mice that had been challenged with bovine BSE cases 74) . This was subsequently crucial information for demonstrating that BSE was associated with the variant CJD cases that were identified in 1996, as the phenotype of the two diseases in mice was indistinguishable, implying that they were caused by the same strain [75][76][77] . ...
Pathology is the study of the structural and functional changes produced by diseases or − more specifically − the lesions they cause. To achieve this pathologists employ various approaches. These include description of lesions that are visible to the naked eye which are the subject of anatomic pathology and changes at the cellular level that are visible under the microscope, the subject of histopathology. Changes at the molecular level which are identified by probes that target specific molecules − mainly proteins that are detected using immunohistochemistry (IHC). As transmissible spongiform encephalopathies (TSEs) do not cause visible lesions anatomic pathology is not applicable to their study. For decades the application of histopathology to detect vacuoles or plaques was the only means of confirming TSE disease. The subsequent discovery of the cellular prion protein (PrPC) and its pathogenic isoform, PrPSc, which is a ubiquitous marker of TSEs, led to the production of anti-PrP antibodies, and enabled the development of PrPSc detection techniques such as immunohistochemistry, Histoblot and PET-blot that have evolved in parallel with similar biochemical methods such as Western blot and ELISA. These methods offer greater sensitivity than histopathology in TSE diagnosis and crucially they can be applied to analyze various phenotypic aspects of single TSE sources increasing the amount of data and offering higher discriminatory power. The above principles are applied to diagnose and define TSE phenotypes which form the basis of strain characterisation.
... While these regions of amino acid similarity are intriguing, ''species barriers'' for prion transmission are undoubtedly more complex . Transmissibility varies from the pattern observed in studies of primates and ungulates when additional species are considered (Brown et al., 1994b;Fraser et al., 1992;Hecker et al., 1992). Inoculation experiments using hamsters have demonstrated the influence on transmissibility of the amino acid similarities from residues 90 to 130 within the three subspecies of hamster (Lowenstein et al., 1990). ...
... While these regions of amino acid similarity are intriguing, ''species barriers'' for prion transmission are undoubtedly more complex . Transmissibility varies from the pattern observed in studies of primates and ungulates when additional species are considered (Brown et al., 1994b;Fraser et al., 1992;Hecker et al., 1992). Inoculation experiments using hamsters have demonstrated the influence on transmissibility of the amino acid similarities from residues 90 to 130 within the three subspecies of hamster (Lowenstein et al., 1990). ...
... For instance, vCJD prions are not transmitted well to transgenic (Tg) mice expressing human PrP (HuPrP) despite the identical amino acid sequences of PrP C and PrP Sc (26). In contrast, vCJD and BSE prions efficiently transmit disease to wild-type (WT) mice (26)(27)(28)(29)(30)(31), although there are many differences in the amino acid sequences between the recipient mouse and the infecting bovine PrP (BoPrP) or HuPrP. The species and strain barriers are often collectively referred to as "transmission barriers" for prion replication, for which a given PrP C can only replicate a subset of PrP Sc conformations (32,33). ...
Importance:
Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the most relevant prion strains to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult due to prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions, but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions.
... Animals were held for over 400 days without signs of clinical disease (scrapie, range 416-594 dpi; classical BSE, range 445-537 dpi; Supplementary Table S2). These data indicate that typical barriers against the transmission of foreign prions from one species of mammal to another were not circumvented by expression of the S1 and S3.F88W PrP alleles (and in this respect did not differ from the performance of WT PrP (Fraser et al, 1992)). Barriers to prion infections can also be caused by PrP coding sequence polymorphism within a species (Carlson et al, 1994). ...
The cellular prion protein (PrP(C)) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrP(S) (c) in Creutzfeldt-Jakob disease. PrP(C) β-endoproteolysis to the C2 fragment allows PrP(S) (c) formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, 'S1' and 'S3', locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrP(S) (c) and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrP(S) (c) and infectivity can either uncouple or engage to drive the onset of clinical disease.
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
... Vacuolation distribution in the Prnp-a mice (RIII and C57BL) show distinctive profiles with higher levels or "peak" of vacuolation in the dorsal medulla, hypothalamus, and septum ( Fig. 1) whereas Prnp-b mice (VM) show peaks in the dorsal medulla, superior colliculus, thalamus, and septum. 2 This BSE signature was confirmed in a number of cases of BSE and was observed in a number of similar transmissions from cats, 3 kudu, and nyala. 4 Thus confirming a single agent was responsible for these new TSE cases in each species. ...
It is now 18 years since the first identification of a case of vCJD in the UK. Since that time there has been much speculation over how vCJD might impact on human health. To date there have been 177 cases reports in the UK and a further 51 cases worldwide in 11 different countries. Since establishing that BSE and vCJD are of the same strain of agent, we have also shown that there is broad similarity between UK and non-UK vCJD cases on first passage to mice. Transgenic mouse studies have indicated that all codon 129 genotypes are susceptible to vCJD and that genotype may influence whether disease appears in a clinical or asymptomatic form, supported by the appearance of the first case of potential asymptomatic vCJD infection in a PRNP 129MV patient. Following evidence of blood transfusion as a route of transmission, we have ascertained that all blood components and leucoreduced blood, in a sheep model of vCJD have the ability to transmit disease. Importantly, we recently established that a PRNP 129MV patient blood recipient with an asymptomatic infection with limited PrP(Sc) deposition in the spleen could readily transmit disease into mice, demonstrating the potential for peripheral infection in the absence of clinical disease. This, along with the recent appendix survey which identified 16 positive appendices in a study of 32 441 cases, underlines the importance of continued CJD surveillance and maintaining control measures already in place to protect human health.
