Markedly Increased Susceptibility to Natural Sheep Scrapie of Transgenic Mice Expressing Ovine PrP

Vilotte, Jean–Luc; Soulier, Solange; Essalmani, Rachid; Stinnakre, Marie‐Georges; Vaiman, Daniel; Lepourry, Laurence; Silva, José Costa da; Besnard, Nathalie; Dawson, Margaret; Buschmann, A.; Groschup, Martin H.; Petit, Stéphanie; Madelaine, M.F.; Rakatobe, Sabine; Dur, Annick Le; Vilette, Didier; Laude, Hubert

doi:10.1128/jvi.75.13.5977-5984.2001

Cited by 166 publications

(202 citation statements)

References 54 publications

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“…The transmission of ∼80 isolates throughout Europe has permitted to classify them into four distinct classes, all being notably different from BSE passaged in sheep or goats ( [20,21,119,197] and our unpublished data), either experimentally or naturally [71]. The molecular behaviours of sheep scrapie isolates in ovine transgenic mice expressing another PrP allele (ARQ mice, [60]) were also variable, suggesting the existence of distinct strains.…”

Section: Assessment Of Scrapie Strain Diversity With Transgenic Mousementioning

confidence: 78%

“…This apparent lack of species barrier after homotypic transmission -i.e. when the host expresses a PrP gene identical to that of the infecting species -has led to the development of a long list of mice transgenic for sheep [60,197,203], bovine [20,41,48,175], human [5,22,113,190], cervid [30,82,113,117,134,188] and mink [206] PrP. Most of such lines were obtained by additional transgenesis, and have an endogenous PrP null (PrP 0/0 ) background, in order to avoid any interfering effect of the resident murine PrP gene [39,190].…”

Section: Influence Of the Prp Genementioning

confidence: 99%

“…Most of such lines were obtained by additional transgenesis, and have an endogenous PrP null (PrP 0/0 ) background, in order to avoid any interfering effect of the resident murine PrP gene [39,190]. An inverse correlation between the length of survival time and expression level of the transgene in the brain has been noticed in mice transgenic for mouse, hamster and sheep PrP [156,197]. Some transgenic lines have been established by a gene replacement method (for review [44]).…”

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Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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Section: Assessment Of Scrapie Strain Diversity With Transgenic Mousementioning

confidence: 78%

Section: Influence Of the Prp Genementioning

confidence: 99%

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confidence: 99%

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Prion agent diversity and species barrier

2008

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“…The demonstration that the BSE agent has almost certainly been transmitted from cattle to human (14,57) has triggered further molecular studies of the abnormal PrP in human and animal TSE, together with the characterization of the infectious agents in murine experimental models (5, 6, 12, 18, 27, 29-31, 52, 53). The recent development of transgenic mice expressing the prion protein of the natural hosts of TSE has offered new opportunities for the biological and molecular characterization of the infectious agents involved in these diseases (15,20,48,54,55).…”

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Molecular Analysis of the Protease-Resistant Prion Protein in Scrapie and Bovine Spongiform Encephalopathy Transmitted to Ovine Transgenic and Wild-Type Mice

Baron¹,

Crozet²,

Biacabe³

et al. 2004

J Virol

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The existence of different strains of infectious agents involved in scrapie, a transmissible spongiform encephalopathy (TSE) of sheep and goats, remains poorly explained. These strains can, however, be differentiated by characteristics of the disease in mice and also by the molecular features of the protease-resistant prion protein (PrP res ) that accumulates into the infected tissues. For further analysis, we first transmitted the disease from brain samples of TSE-infected sheep to ovine transgenic [Tg(OvPrP4)] and to wild-type (C57BL/6) mice. We show that, as in sheep, molecular differences of PrP res detected by Western blotting can differentiate, in both ovine transgenic and wild-type mice, infection by the bovine spongiform encephalopathy (BSE) agent from most scrapie sources. Similarities of an experimental scrapie isolate (CH1641) with BSE were also likewise found following transmission in ovine transgenic mice. Secondly, we transmitted the disease to ovine transgenic mice by inoculation of brain samples of wild-type mice infected with different experimental scrapie strains (C506M3, 87V, 79A, and Chandler) or with BSE. Features of these strains in ovine transgenic mice were reminiscent of those previously described for wild-type mice, by both ratios and by molecular masses of the different PrP res glycoforms. Moreover, these studies revealed the diversity of scrapie strains and their differences with BSE according to labeling by a monoclonal antibody (P4). These data, in an experimental model expressing the prion protein of the host of natural scrapie, further suggest a genuine diversity of TSE infectious agents and emphasize its linkage to the molecular features of the abnormal prion protein.

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“…Transgenic mouse lines displaying a short incubation period with a given prion strain must therefore not necessarily have a high susceptibility to all other strains derived from the same species. For example in Tg338 mice overexpressing ovine PrP C (VRQ allele), incubation times for primary ovine scrapie isolates can vary from 60 days (ARQ allele PG127) [84] to well over 600 days (for individual Italian scrapie isolates) 2 . However, a prion strain with a shorter incubation time has the potential to be detected more efficiently since the natural life span of a mouse is limited to approximately two years.…”

Section: Assessment Of Species Barrier Effects In Heterologous Transgmentioning

confidence: 99%

Rodent models for prion diseases

Groschup

Buschmann

2008

Vet. Res.

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-Until today most prion strains can only be propagated and the infectivity content assayed by experimentally challenging conventional or transgenic animals. Robust cell culture systems are not available for any of the natural and only for a few of the experimental prion strains. Moreover, the pathogenesis of different transmissible spongiform encephalopathies (TSE) can be analysed systematically by using experimentally infected animals. While, in the beginning, animals belonging to the natural host species were used, more and more rodent model species have been established, mostly due to practical reasons. Nowadays, most of these experiments are performed using highly susceptible transgenic mouse lines expressing cellular prion proteins, PrP, from a variety of species like cattle, sheep, goat, cervidae, elk, hamster, mouse, mink, pig, and man. In addition, transgenic mice carrying specific mutations or polymorphisms have helped to understand the molecular pathomechanisms of prion diseases. Transgenic mouse models have been utilised to investigate the physiological role of PrP C , molecular aspects of species barrier effects, the cell specificity of the prion propagation, the role of the PrP glycosylation, the mechanisms of the prion spread, the neuropathological roles of PrP C and of its abnormal isoform PrP D (D for disease) as well as the function of PrP Doppel. Transgenic mouse models have also been used for mapping of PrP regions involved in or required for the PrP conversion and prion replication as well as for modelling of familial forms of human prion diseases.

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Markedly Increased Susceptibility to Natural Sheep Scrapie of Transgenic Mice Expressing Ovine PrP

Cited by 166 publications

References 54 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Molecular Analysis of the Protease-Resistant Prion Protein in Scrapie and Bovine Spongiform Encephalopathy Transmitted to Ovine Transgenic and Wild-Type Mice

Rodent models for prion diseases

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