Assessment of the Genetic Susceptibility of Sheep to Scrapie by Protein Misfolding Cyclic Amplification and Comparison with Experimental Scrapie Transmission Studies

Bucalossi, Cecilia; Cosseddu, Gian Mario; D’Agostino, Claudia; Bari, Michele Angelo Di; Chiappini, Barbara; Conte, Michela; Rosone, Francesca; Grossi, Luigi De; Scavia, Gaia; Agrimi, Umberto; Nonno, Romolo; Vaccari, Gabriele

doi:10.1128/jvi.00241-11

Cited by 32 publications

(27 citation statements)

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“…In vitro cell-free conversion efficiencies have been demonstrated to inversely correlate with natural or experimental scrapie or BSE transmission incubation times in sheep of homozygous or heterozygous PrP genotypes (64,65). Extrapolating relative susceptibilities to homozygous counterparts from these measurements using heterozygous animals might be risky since one allelic variant might contribute more or less significantly to the conversion process.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies

Priem

Langeveld

Keulen

et al. 2014

J Virol

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Bovine spongiform encephalopathy (BSE) can be efficiently transmitted to small ruminants (sheep and goats) with certain prion protein (PrP) genotypes. Polymorphisms in PrP of both the host and donor influence the transmission efficiency of transmissible spongiform encephalopathies (TSEs) in general. These polymorphisms in PrP also modulate the PrP conversion underlying TSE agent replication. Here we demonstrate that single-round protein misfolding cyclic amplification (PMCA) can be used to assess species and polymorphism barriers at the molecular level. We assessed those within and between the ovine and bovine species in vitro using a variety of natural scrapie and experimentally generated cross-species BSE agents. These BSE agents include ovBSE-ARQ isolates (BSE derived from sheep having the ARQ/ARQ PrP genotype), and two unique BSE-derived variants: BSE passaged in VRQ/VRQ sheep and a cow BSE agent isolate generated by back-transmission of ovBSE-ARQ into its original host. PMCA allowed us to quantitatively determine PrP conversion profiles that correlated with known in vivo transmissibility and susceptibility in the two ruminant species in which strain-specific molecular signatures, like its molecular weight after protease digestion, were maintained. Furthermore, both BSE agent isolates from ARQ and VRQ sheep demonstrated a surprising transmission profile in which efficient transmissions to both sheep and bovine variants was combined. Finally, all data support the notion that ARQ-derived sheep BSE points to a significant increase in virulence compared to all other tested scrapie-and BSE-derived variants reflected by the increased conversion efficiencies of previously inefficient convertible PrP variants (including the so-called "resistant" sheep ARR variant). IMPORTANCEPrion diseases such as scrapie in sheep and goats, BSE in cattle, and Creutzfeldt-Jakob disease (CJD) in humans are fatal neurodegenerative diseases caused by prions. BSE is known to be transmissible to a variety of hosts, including sheep and humans. Based on the typical BSE agent strain signatures and epidemiological data, the occurrence of a novel variant of CJD in humans was linked to BSE occurrence in the United Kingdom. Measures, including genetic selection of sheep toward less susceptible PrP genotypes, have been implemented to lower the risk of BSE transmission into sheep, since the disease could potentially spread into a natural reservoir. In this study, we demonstrated using molecular PrP conversion studies that when BSE is first transmitted through sheep, the host range is modified significantly and the PrP converting potency increased, allowing the ovine BSE to transmit more efficiently than cow BSE into supposedly less susceptible hosts. P rion diseases, or transmissible spongiform encephalopathies (TSEs), include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs in sheep and cattle are naturally occurring infectious and fatal neurological disorde...

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Section: Discussionmentioning

confidence: 99%

Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies

Priem

Langeveld

Keulen

et al. 2014

J Virol

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“…All CDJ afected individuals are known to be homozygous for methionine amino acid in codon 129 while at the same codon heterozygote individuals seem most resistant to kuru [4,5]. Also, it is known that there is a high correlation between the polymorphisms in codons 136,154, and 171 of the PRNP gene and the level of susceptibility to scrapie in sheep [3,6,7]. In catle, numerous studies were carried out for discovering a relationship amongst BSE and polymorphisms in catle genome [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Polymorphisms inside the prion protein-coding gene (PRNP) in humans and also in some mammalian species have been appeared to impact disease susceptibility and pathologies [3]. In human population, kuru and CJD are profoundly related with polymorphism in codon 129.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Resistance to Prion Diseases

Yaman¹,

Ün²

2017

Prion - An Overview

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Prions are abnormal isoforms of the host-encoded cellular prion proteins which are misfolding in its three-dimensional structure acquire pathogenicity. Prions cause transmissible spongiform encephalopathy (TSEs) in humans and some animal species including sheep, goats, catle, cat, deer and elk. TSEs, also called "prion diseases," cause irreversible neurodegeneration in the central nervous system and are always fatal. Cellular prion proteins are encoded by prion protein gene (PRNP) in mammals; moreover, it is known that the variations in the PRNP gene have inluence on the resistance and/or incubation period of the TSEs. It is well-documented that after exposure to the pathogenic prions, development of some TSEs depend on the host PRNP genotype, for example, scrapie in sheep, bovine spongiform encephalopathy (BSE) in catle, Creuzfeldt-Jakob disease (CJD) and kuru in humans, as well. In this chapter, genetic resistance to prion diseases will be reviewed.Keywords: TSE, prion disease, PRNP, genetic resistance IntroductionIt is known that conformational changes in prion protein cause Creuzfeldt-Jakob disease (CJD) in humans, scrapie disease in sheep and goats [1,2], bovine spongiform encephalopathy (BSE) in catle, feline spongiform encephalopathy in cat, and wasting disease in deer and elk.Polymorphisms inside the prion protein-coding gene (PRNP) in humans and also in some mammalian species have been appeared to impact disease susceptibility and pathologies [3]. In human population, kuru and CJD are profoundly related with polymorphism in codon 129. All CDJ afected individuals are known to be homozygous for methionine amino acid in codon 129 while at the same codon heterozygote individuals seem most resistant to kuru [4,5]. Also, it is known that there is a high correlation between the polymorphisms in codons © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.136, 154, and 171 of the PRNP gene and the level of susceptibility to scrapie in sheep [3,6,7]. In catle, numerous studies were carried out for discovering a relationship amongst BSE and polymorphisms in catle genome [8][9][10][11][12]. The studies about BSE-afected animals in Germany and USA represented the inluence of PRNP promoter polymorphisms on BSE susceptibility in catle [13,14]. The impacts of insertion-deletion (indel) polymorphisms within a location 1.6 kbp upstream of exon 1 and inside intron 1 (23-bp and 12-bp, respectively) on BSE susceptibility are determined by further analyses in catle [15][16][17]. Despite the fact that catle with the -/-23 bp promoter genotype and the -/12 bp intron 1 genotype have both been signiicantly connected with BSE, it could not be reached any consensus on which genotype is most identiied with BSE [13,15,16,18]. In addition, indel polymorphisms that afect the sensitivity o...

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“…Sarda sheep breed shows two alleles associated to classical scrapie resistance, AT137RQ and ARQK176 (Maestrale et al, 2009;Vaccari et al, 2009;Bucalossi et al, 2011). In a clinical study that involved the Barbado breed, heterozygous ARQ-ARK171 showed a prolonged average incubation time of 30 months before the onset of clinical signs (Greenlee et al, 2012) and similarly, in infected Suffolk sheep, heterozygous AM112RQ-AT112RQ showed lower attack and increased survival rates (Chianini et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Biodiversity and Genetic Polymorphisms Against Scrapie inSopravissanaSheep Breed

Curcio

Lasagna

Sarti

et al. 2015

Italian Journal of Animal Science

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Scrapie is a neurodegenerative disease affecting ovine and it is one of several transmissible spongiform encephalopathies (TSEs). Scrapie is recognized as two forms -classical and atypical. Susceptibility or resistance to classical scrapie is strongly regulated by the polymorphisms at codons 136, 154 and 171 of the PRNP gene. Genetic role in atypical scrapie has been described at codons 141 and 154, these ones are involved in the occurrence of the disease at different risk degrees. The aim of this study was to assess the allelic and genotypic frequencies in Sopravissana breed, an endangered autochthon breed of central Italy; in addition, the presence and the frequency of potential protective ARQ allele variants able to increase scrapie resistance by preserving a higher variability of PRNP were evaluated. Three alleles (ARQ, ARR and AHQ) and seven genotypes were observed based on codons 136, 154 and 171 with different frequencies. Moreover, the entire coding sequence of prion protein (PRNP) of the ARQ/ARQ was sequenced; two non-synonymous L141F (23.8%) and H143R (16.7%), also two synonymous polymorphisms (codons 231 and 237) were found. The results showed that the ARQ/ARQ sheep should be considered as a genetic class, which may potentially include animals with different scrapie susceptibility because of the presence of additional polymorphisms. This may allow the application of alternative strategies for breeding programmes in this endangered breed.

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Assessment of the Genetic Susceptibility of Sheep to Scrapie by Protein Misfolding Cyclic Amplification and Comparison with Experimental Scrapie Transmission Studies

Cited by 32 publications

References 50 publications

Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies

Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies

Genetic Resistance to Prion Diseases

Biodiversity and Genetic Polymorphisms Against Scrapie inSopravissanaSheep Breed

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