Prion protein genetics: Host PrP control of TSE susceptibility

TSEs (transmissible spongiform encephalopathies) are fatal, degenerative disorders of the central nervous system. The best-known members of this disease family are sheep scrapie, cattle BSE (bovine spongiform encephalopathy) and human CJD (Creutzfeldt–Jakob disease). By far the most important host gene in TSEs is the PrP (prion protein) gene. It modulates TSE susceptibility at many levels and is the crucial element in the treatment and eradication of these diseases. This article will highlight the advances in our understanding of PrP genetics in animals and man.

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Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein

Journal of General Virology ◽

10.1099/vir.0.042507-0 ◽

2012 ◽

Vol 93 (7) ◽

pp. 1624-1629 ◽

Cited By ~ 52

Author(s):

Rona Wilson ◽

Chris Plinston ◽

Nora Hunter ◽

Cristina Casalone ◽

Cristiano Corona ◽

...

Keyword(s):

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Chronic Wasting Disease ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Wild Type ◽

Wasting Disease ◽

Spongiform Encephalopathies ◽

Jakob Disease ◽

Human Prion Protein

The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt–Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.

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Pathological prion protein in muscles of hamsters and mice infected with rodent-adapted BSE or vCJD

Journal of General Virology ◽

10.1099/vir.0.81277-0 ◽

2006 ◽

Vol 87 (1) ◽

pp. 251-254 ◽

Cited By ~ 22

Author(s):

Achim Thomzig ◽

Franco Cardone ◽

Dominique Krüger ◽

Maurizio Pocchiari ◽

Paul Brown ◽

...

Keyword(s):

Public Health ◽

Prion Protein ◽

Health Risks ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Spongiform Encephalopathies ◽

Mammalian Muscle ◽

Public Health Risks ◽

Jakob Disease ◽

First Time

Recently, pathological prion protein (PrPTSE) was detected in muscle from sheep infected with scrapie, the archetype of transmissible spongiform encephalopathies (TSEs). This finding has highlighted the question of whether mammalian muscle may potentially also provide a reservoir for TSE agents related to bovine spongiform encephalopathy (BSE) and variant Creutzfeldt–Jakob Disease (vCJD). Here, results are reported from studies in hamsters and mice that provide direct experimental evidence, for the first time, of BSE- and vCJD-associated PrPTSE deposition in muscles. Our findings emphasize the need for further assessment of possible public-health risks from TSE involvement of skeletal muscle.

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Prion-protein-related diseases of animals and man

10.1093/med/9780198570028.003.0041 ◽

2011 ◽

Author(s):

James Hope ◽

Mark P. Dagleish

Keyword(s):

Prion Protein ◽

Large Scale ◽

Spongiform Encephalopathy ◽

Variant Form ◽

Spongiform Encephalopathies ◽

Peripheral Tissues ◽

Disease Characteristics ◽

Jakob Disease ◽

The Central Nervous System ◽

Iatrogenic Transmission

Scrapie, bovine spongiform encephalopathy (BSE), Creutzfeldt–Jakob disease (CJD), and related diseases of mink (transmissible mink encephalopathy), mule deer and elk (chronic wasting disease) are the founder members of a group of diseases called the transmissible degenerative (or spongiform) encephalopathies (TSE). These diseases can be transmitted by prions from affected to healthy animals by inoculation or by feeding diseased tissues. Prions are cellular proteins that can transfer metabolic and pathological phenotypes vertically from parent to progeny or horizontally between cells and animals. TSEs are characterised by the accumulation of the prion form of the mammalian prion protein (PrPC) in the central nervous system or peripheral tissues of animals and humans. Mutations of the human PrP gene are linked to rare, familial forms of disease and prion-protein gene polymorphisms in humans and other species are linked to survival time and disease characteristics in affected individuals. Iatrogenic transmission of CJD in man has occurred, and a variant form of CJD (vCJD) is due to cross-species transmission of BSE from cattle to humans. Atypical forms of scrapie and BSE have been identified during large-scale monitoring for TSEs worldwide. This chapter outlines our current understanding of scrapie, BSE, CJD and other TSEs and highlights recent progress in defining the role in disease of the prion protein, PrP.

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How to Limit the Spread of Creutzfeldt-Jakob Disease

Infection Control and Hospital Epidemiology ◽

10.1017/s0195941700004720 ◽

1996 ◽

Vol 17 (8) ◽

pp. 521-528

Author(s):

Dominique Dormont

Keyword(s):

Blood Donation ◽

Transmissible Spongiform Encephalopathy ◽

Infected Individual ◽

Experimental Models ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Spongiform Encephalopathies ◽

Corneal Grafting ◽

Jakob Disease ◽

Spleen And Lymph Nodes

AbstractTransmissible spongiform encephalopathies are rare lethal diseases induced in humans and animals by unconventional agents called transmissible spongiform encephalopathy agents (TSEAs), virions, or prions. Several cases of iatrogenic Creutzfeldt-Jakob disease (CJD) have been reported in the literature after neuro-surgery, treatment with pituitary-derived hormones, corneal grafting, and use of dura mater lyophilisates. In a given infected individual, TSEA-associated infectiousness depends on the nature of the organ: the central nervous system has the highest infectiousness, spleen and lymph nodes a medium infectiousness, and organs such as bone, skin, or skeletal muscles do not harbor any detectable infectiousness in experimental models. Transmissible spongiform encephalopathy/prions have unconventional properties; in particular, they resist almost all the chemical and physical processes that inactivate conventional viruses. Therefore, prevention of CJD agent transmission must be taken into account in daily hospital practice. Efficient sterilization procedures should be determined. In tissue and blood donation, donors with a neurologic history must be excluded, and patients treated with pituitary-derived hormones should be considered potentially infected with TSEA and excluded.

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Sympathetic Prions

The Scientific World JOURNAL ◽

10.1100/tsw.2001.258 ◽

2001 ◽

Vol 1 ◽

pp. 555-556 ◽

Cited By ~ 4

Author(s):

Markus Glatzel

Keyword(s):

Gastrointestinal Tract ◽

Injection Site ◽

Peripheral Nerves ◽

Infectious Agent ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Membrane Glycoprotein ◽

Spongiform Encephalopathies ◽

Jakob Disease ◽

The Brain

Transmissible spongiform encephalopathies are a group of invariably fatal neurodegenerative diseases. The infectious agent is termed prion and is thought to be composed of a modified protein (PrPSc or PrPRES), a protease-resistant conformer of the normal host-encoded membrane glycoprotein, PrPC[1]. Bovine spongiform encephalopathy, scrapie of sheep, and Creutzfeldt-Jakob disease are among the most notable transmissible spongiform encephalopathies. Prions are most efficiently propagated trough intracerebral inoculation, yet the entry point of the infectious agent is often through peripheral sites like the gastrointestinal tract[2,3]. The process by which prions invade the brain is termed neuroinvasion[4]. We and others have speculated that, depending on the amount of infectious agent injected, the injection site, and the strain of prions employed, neuroinvasion can occur either directly via peripheral nerves or first through the lymphoreticular system and then via peripheral nerves[5].

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Scrapie susceptibility-associated indel polymorphism of shadow of prion protein gene (SPRN) in Korean native black goats

Scientific Reports ◽

10.1038/s41598-019-51625-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Yong-Chan Kim ◽

Seon-Kwan Kim ◽

Byung-Hoon Jeong

Keyword(s):

Prion Protein ◽

Protein Gene ◽

Allele Frequencies ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Prion Protein Gene ◽

Indel Polymorphism ◽

Spongiform Encephalopathies ◽

Direct Dna Sequencing ◽

Significant Difference

Abstract Prion diseases in sheep and goats are called scrapie and belong to a group of transmissible spongiform encephalopathies (TSEs) caused by the abnormal misfolding of the prion protein encoded by the prion protein gene (PRNP). The shadow of the prion protein gene (SPRN) is the only prion gene family member that shows a protein expression profile similar to that of the PRNP gene in the central nervous system. In addition, genetic susceptibility of the SPRN gene has been reported in variant Creutzfeldt–Jakob disease (CJD), bovine spongiform encephalopathy (BSE) and scrapie. However, genetic studies of the SPRN gene have not been carried out in Korean native black goats. Here, we investigated the genotype and allele frequencies of SPRN polymorphisms in 213 Korean native black goats and compared these polymorphisms with those previously reported for scrapie-affected animals. We found a total of 6 polymorphisms including 1 nonsynonymous single nucleotide polymorphism (SNP) and 1 synonymous SNP in the open reading frame (ORF) region and 3 SNPs and 1 indel polymorphism (c.495_496insCTCCC) in the 3′ untranslated region (UTR) by direct DNA sequencing. A significant difference in the allele frequency of the c.495_496insCTCCC indel polymorphism was found between the Italian scrapie-affected goats and the Korean native black goats (P < 0.001). Furthermore, there was a significant difference in the allele frequencies of the c.495_496insCTCCC indel polymorphism between Italian healthy goats and Korean native black goats (P < 0.001). To evaluate the biological impact of the novel nonsynonymous SNP c.416G > A (Arg139Gln), we carried out PROVEAN analysis. PROVEAN predicted the SNP as ‘Neutral’ with a score of −0.297. To the best of our knowledge, this is the first genetic study of the SPRN gene in Korean native black goats.

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Prion Type-Dependent Deposition ofPRNPAllelic Products in Heterozygous Sheep

Journal of Virology ◽

10.1128/jvi.02316-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 805-812 ◽

Cited By ~ 7

Author(s):

J. P. M. Langeveld ◽

J. G. Jacobs ◽

N. Hunter ◽

L. J. M. van Keulen ◽

F. Lantier ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Sequence ◽

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Transmissible Spongiform Encephalopathy ◽

Infected Sheep ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Sequence Variants ◽

Spongiform Encephalopathies

ABSTRACTSusceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, PrP allotype composition in protease-resistant prion protein (PrPres) from brain of heterozygous ARR/VRQ scrapie-infected sheep was compared with that of BSE-infected sheep with a similar genotype. A triplex Western blotting technique was used to estimate the two allotype PrP fractions in PrPresmaterial from BSE-infected ARR/VRQ sheep. PrPresin BSE contained equimolar amounts of VRQ- and ARR-PrP, which contrasts with the excess (>95%) VRQ-PrP fraction found in PrP in scrapie. This is evidence that transmissible spongiform encephalopathy (TSE) agent properties alone, perhaps structural aspects of prions (such as PrP amino acid sequence variants and PrP conformational state), determine the polymorphic dependence of the PrPresaccumulation process in prion formation as well as the disease-associated phenotypic expressions in the host.IMPORTANCETransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative and transmissible diseases caused by prions. Amino acid sequence variants of the prion protein (PrP) determine transmissibility in the hosts, as has been shown for classical scrapie in sheep. Each individual produces a separate PrP molecule from its two PrP gene copies. Heterozygous scrapie-infected sheep that produce two PrP variants associated with opposite scrapie susceptibilities (136V-PrP variant, high; 171R-PrP variant, very low) contain in their prion material over 95% of the 136V PrP variant. However, when these sheep are infected with prions from cattle (bovine spongiform encephalopathy [BSE]), both PrP variants occur in equal ratios. This shows that the infecting prion type determines the accumulating PrP variant ratio in the heterozygous host. While the host's PrP is considered a determining factor, these results emphasize that prion structure plays a role during host infection and that PrP variant involvement in prions of heterozygous carriers is a critical field for understanding prion formation.

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Quinoline Derivatives Are Therapeutic Candidates for Transmissible Spongiform Encephalopathies

Journal of Virology ◽

10.1128/jvi.78.3.1281-1288.2004 ◽

2004 ◽

Vol 78 (3) ◽

pp. 1281-1288 ◽

Cited By ~ 58

Author(s):

Ikuko Murakami-Kubo ◽

Katsumi Doh-ura ◽

Kensuke Ishikawa ◽

Satoshi Kawatake ◽

Kensuke Sasaki ◽

...

Keyword(s):

Incubation Period ◽

Prion Protein ◽

Neuroblastoma Cells ◽

Transmissible Spongiform Encephalopathies ◽

Side Chain ◽

Spongiform Encephalopathy ◽

Quinoline Derivatives ◽

Quinoline Ring ◽

Spongiform Encephalopathies ◽

Dose Ranging

ABSTRACT We previously reported that quinacrine inhibited the formation of an abnormal prion protein (PrPres), a key molecule in the pathogenesis of transmissible spongiform encephalopathy, or prion disease, in scrapie-infected neuroblastoma cells. To elucidate the structural aspects of its inhibiting action, various chemicals with a quinoline ring were screened in the present study. Assays of the scrapie-infected neuroblastoma cells revealed that chemicals with a side chain containing a quinuclidine ring at the 4 position of a quinoline ring (represented by quinine) inhibited the PrPres formation at a 50% inhibitory dose ranging from 10−1 to 101 μM. On the other hand, chemicals with a side chain at the 2 position of a quinoline ring (represented by 2,2′-biquinoline) more effectively inhibited the PrPres formation at a 50% inhibitory dose ranging from 10−3 to 10−1 μM. A metabolic labeling study revealed that the action of quinine or biquinoline was not due to any alteration in the biosynthesis or turnover of normal prion protein, whereas surface plasmon resonance analysis showed a strong binding affinity of biquinoline with a recombinant prion protein. In vivo studies revealed that 4-week intraventricular infusion of quinine or biquinoline was effective in prolonging the incubation period in experimental mouse models of intracerebral infection. The findings suggest that quinoline derivatives with a nitrogen-containing side chain have the potential of both inhibiting PrPres formation in vitro and prolonging the incubation period of infected animals. These chemicals are new candidates for therapeutic drugs for use in the treatment of transmissible spongiform encephalopathies.

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Prion Diseases and the Gastrointestinal Tract

Canadian Journal of Gastroenterology ◽

10.1155/2006/184528 ◽

2006 ◽

Vol 20 (1) ◽

pp. 18-24 ◽

Cited By ~ 21

Author(s):

Gwynivere A Davies ◽

Adam R Bryant ◽

John D Reynolds ◽

Frank R Jirik ◽

Keith A Sharkey

Keyword(s):

Nervous System ◽

Dendritic Cells ◽

Enteric Nervous System ◽

Prion Protein ◽

Cellular Prion Protein ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Gi Tract ◽

Spongiform Encephalopathies ◽

The Brain

The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Alhough they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPscpropagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer’s patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPscin the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.

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Copper and prion diseases

Biochemical Society Transactions ◽

10.1042/bst0300742 ◽

2002 ◽

Vol 30 (4) ◽

pp. 742-745 ◽

Cited By ~ 16

Author(s):

D. R. Brown

Keyword(s):

Prion Protein ◽

Strong Evidence ◽

Prion Diseases ◽

Transmissible Spongiform Encephalopathies ◽

Normal Brain ◽

Spongiform Encephalopathies ◽

Metal Metabolism ◽

Jakob Disease ◽

Anti Oxidant ◽

Experimental Mouse

Transmissible spongiform encephalopathies are diseases of animals and humans that are also termed prion diseases. These diseases are linked together because a normal brain glycoprotein termed the prion protein is converted to a readily detectable protease-resistant isoform. There is now strong evidence to suggest that apart from this difference in resistance a major difference between the isoforms is that the normal prion protein binds copper and has an anti-oxidant function. Brains from Creutzfeldt-Jakob disease patients and brains from mice with experimental mouse scrapie have been shown to have changes in the levels of both copper and manganese. There is growing evidence that links prion diseases to disturbances of metal metabolism.

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