Transgenic Rabbits Expressing Ovine PrP Are Susceptible to Scrapie

Sarradin, Pierre; Viglietta, Céline; Limouzin, Claude; Andréoletti, Olivier; Daniel-Carlier, Nathalie; Barc, Céline; Leroux-Coyau, Mathieu; Berthon, Patricia; Chapuis, Jérôme; Rossignol, Christelle; Gatti, Jean‐Luc; Belghazi, Maya; Labas, Valérie; Vilotte, Jean Luc; Béringue, Vincent; Lantier, Frédéric; Laude, Hubert; Houdebiné, Louis‐Marie

doi:10.1371/journal.ppat.1005077

Cited by 15 publications

(14 citation statements)

References 44 publications

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“…Adding and removing PrP C at different stages of experimentally induced prion disease could be used to determine when PrP C lossof-function is important for disease progression. We propose that expanding this approach by deploying transgenic variants of PrP C that are seemingly inert to protein misfolding, such as rabbit PrP C [158], would allow one to assess outcomes when PrP C is not reduced in abundance or misfolded (i.e., the transgene would rescue the loss-of-function) and yet presumably would not be contributing to further gain-of-function etiology. A potential caveat of the proposed experiment is that expression of rabbit PrP C may interfere with the gain-of-function conversion of PrP C to its misfolded form and its associated toxicity, as has previously been the case when heterologous pools of PrP C are present [122].…”

Section: Disease Gene Mutationmentioning

confidence: 99%

Protein Misfolding in Prion and Prion-Like Diseases: Reconsidering a Required Role for Protein Loss-of-Function

Leighton

Allison

2016

JAD

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Prion disease research has contributed much toward understanding other neurodegenerative diseases, including recent demonstrations that Alzheimer's disease (AD) and other neurodegenerative diseases are prion-like. Prion-like diseases involve the spread of degeneration between individuals and/or among cells or tissues via template directed misfolding, wherein misfolded protein conformers propagate disease by causing normal proteins to misfold. Here we use the premise that AD, amyotrophic lateral sclerosis, Huntington's disease, and other similar diseases are prion-like and ask: Can we apply knowledge gained from studies of these prion-like diseases to resolve debates about classical prion diseases? We focus on controversies about what role(s) protein loss-of-function might have in prion diseases because this has therapeutic implications, including for AD. We examine which loss-of-function events are recognizable in prion-like diseases by considering the normal functions of the proteins before their misfolding and aggregation. We then delineate scenarios wherein gain-of-function and/or loss-of-function would be necessary or sufficient for neurodegeneration. We consider roles of PrPC loss-of-function in prion diseases and in AD, and conclude that the conventional wisdom that prion diseases are 'toxic gain-of-function diseases' has limitations. While prion diseases certainly have required gain-of-function components, we propose that disease phenotypes are predominantly caused by deficits in the normal physiology of PrPC and its interaction partners as PrPC converts to PrPSc. In this model, gain-of-function serves mainly to spread disease, and loss-of-function directly mediates neuron dysfunction. We propose experiments and predictions to assess our conclusion. Further study on the normal physiological roles of these key proteins is warranted.

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Section: Disease Gene Mutationmentioning

confidence: 99%

Protein Misfolding in Prion and Prion-Like Diseases: Reconsidering a Required Role for Protein Loss-of-Function

Leighton

Allison

2016

JAD

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“…The existence of some PrP-independent, species-specific unknown factors (13) as an explanation for the apparent resistance of some species to TSEs was ruled out recently by successful transmission to transgenic rabbits. The generation of transgenic rabbits expressing ovine PrP and their successful infection with scrapie prions definitively highlighted that the amino acid sequence of rabbit PrP C was responsible for the low susceptibility of rabbits to prion infections (14). Although rabbit PrP C has been studied in detail to identify distinctive structural elements that explain its low susceptibility to prion-like misfolding (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), the key elements or amino acid residues causing this behavior remain unknown.…”

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confidence: 99%

In Vitro Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding

Eraña

Fernández‐Borges

Elezgarai

et al. 2017

J Virol

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Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of rare progressive neurodegenerative disorders caused by an abnormally folded prion protein (PrP). This is capable of transforming the normal cellular prion protein (PrP) into new infectious PrP Interspecies prion transmissibility studies performed by experimental challenge and the outbreak of bovine spongiform encephalopathy that occurred in the late 1980s and 1990s showed that while some species (sheep, mice, and cats) are readily susceptible to TSEs, others are apparently resistant (rabbits, dogs, and horses) to the same agent. To study the mechanisms of low susceptibility to TSEs of certain species, the mouse-rabbit transmission barrier was used as a model. To identify which specific amino acid residues determine high or low susceptibility to PrP propagation, protein misfolding cyclic amplification (PMCA), which mimics PrP-to-PrP conversion with accelerated kinetics, was used. This allowed amino acid substitutions in rabbit PrP and accurate analysis of misfolding propensities. Wild-type rabbit recombinant PrP could not be misfolded into a protease-resistant self-propagating isoform despite seeding with at least 12 different infectious prions from diverse origins. Therefore, rabbit recombinant PrP mutants were designed to contain every single amino acid substitution that distinguishes rabbit recombinant PrP from mouse recombinant PrP. Key amino acid residue substitutions were identified that make rabbit recombinant PrP susceptible to misfolding, and using these, protease-resistant misfolded recombinant rabbit PrP was generated. Additional studies characterized the mechanisms by which these critical amino acid residue substitutions increased the misfolding susceptibility of rabbit PrP. Prion disorders are invariably fatal, untreatable diseases typically associated with long incubation periods and characteristic spongiform changes associated with neuronal loss in the brain. Development of any treatment or preventative measure is dependent upon a detailed understanding of the pathogenesis of these diseases, and understanding the mechanism by which certain species appear to be resistant to TSEs is critical. Rabbits are highly resistant to naturally acquired TSEs, and even under experimental conditions, induction of clinical disease is not easy. Using recombinant rabbit PrP as a model, this study describes critical molecular determinants that confer this high resistance to transmissible spongiform encephalopathies.

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“…To study whether the genetic background of rabbits was responsible for the apparent prion resistance, Houdebine’s group generated transgenic rabbits expressing an ovine PrP C which was known to easily misfold. Upon inoculation with ovine prion strains these rabbits succumbed to prion disease further proving that rabbits are not resistant to prions (results published paired with this article) and that the genetic background is not a limiting factor [ 37 ].…”

Section: Discussionmentioning

confidence: 86%

“…Houdebine’s group studied whether the genetic background of rabbits was responsible for their apparent prion resistance generated transgenic rabbits expressing ovine PrP C . Upon inoculation with scrapie, these rabbits succumbed to prion disease further proving that leporids are not resistant to prion disease [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

Transgenic Mouse Bioassay: Evidence That Rabbits Are Susceptible to a Variety of Prion Isolates

et al. 2015

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Interspecies transmission of prions is a well-established phenomenon, both experimentally and under field conditions. Upon passage through new hosts, prion strains have proven their capacity to change their properties and this is a source of strain diversity which needs to be considered when assessing the potential risks associated with consumption of prion contaminated protein sources. Rabbits were considered for decades to be a prion resistant species until proven otherwise recently. To determine the extent of rabbit susceptibility to prions and to assess the effects of passage of different prion strains through this species a transgenic mouse model overexpressing rabbit PrPC was developed (TgRab). Intracerebral challenges with prion strains originating from a variety of species including field isolates (ovine SSBP/1 scrapie, Nor98- scrapie; cattle BSE, BSE-L and cervid CWD), experimental murine strains (ME7 and RML) and experimentally obtained ruminant (sheepBSE) and rabbit (de novo NZW) strains were performed. On first passage TgRab were susceptible to the majority of prions (Cattle BSE, SheepBSE, BSE-L, de novo NZW, ME7 and RML) tested with the exception of SSBP/1 scrapie, CWD and Nor98 scrapie. Furthermore, TgRab were capable of propagating strain-specific features such as differences in incubation periods, histological brain lesions, abnormal prion (PrPd) deposition profiles and proteinase-K (PK) resistant western blotting band patterns. Our results confirm previous studies proving that rabbits are not resistant to prion infection and show for the first time that rabbits are susceptible to PrPd originating in a number of other species. This should be taken into account when choosing protein sources to feed rabbits.

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Transgenic Rabbits Expressing Ovine PrP Are Susceptible to Scrapie

Cited by 15 publications

References 44 publications

Protein Misfolding in Prion and Prion-Like Diseases: Reconsidering a Required Role for Protein Loss-of-Function

Protein Misfolding in Prion and Prion-Like Diseases: Reconsidering a Required Role for Protein Loss-of-Function

In Vitro Approach To Identify Key Amino Acids in Low Susceptibility of Rabbit Prion Protein to Misfolding

Transgenic Mouse Bioassay: Evidence That Rabbits Are Susceptible to a Variety of Prion Isolates

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