The shifting biology of prions

doi:10.1016/S0165-0173(01)00100-X

Brain Research Reviews

Volume 36, Issues 2–3, October 2001, Pages 241-248

https://doi.org/10.1016/S0165-0173(01)00100-X Get rights and content

Abstract

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are rare fatal neurodegenerative diseases of humans and animals. Although some TSEs, like scrapie in sheep, have been known to exist for centuries, bovine spongiform encephalopathy (BSE) was recognized only 15 years ago. New variant Creutzfeldt–Jakob disease (nvCJD) of humans is probably caused by consumption of BSE-infected materials. The nature of the infectious agent is not fully elucidated, but substantial evidence suggests that it is devoid of nucleic acids and consists at least in part of an abnormal form of a host protein termed PrP^C. Despite their rarity, prion diseases have become an important topic in public health and basic research because of the connection between nvCJD and BSE and also because of the unusual biological attributes of the infectious agent.

Introduction

Prion (from proteinaceous infectious only) diseases are a unique group of illnesses because they are both inheritable and infectious. A common feature of all prion diseases is the aberrant metabolism of the prion protein (PrP). PrP exists in at least two conformational states with distinct physicochemical properties. The cellular form of the prion protein (referred to as PrP^C) is a membrane-bound protein of unknown function. It is expressed at high levels in neurons and in lower levels in cells of the immune system and in muscle [5]. The structure of PrP^C has been resolved by nuclear magnetic resonance studies. It comprises three α-helices and a C-terminal globular domain. The disease-associated isoform of PrP^C is termed PrP^Sc. In contrast to PrP^C, PrP^Sc is detergent-insoluble and partially protease-resistant. Although the precise structure of PrP^Sc is not known, biophysical evidence points towards a high β-sheet content.

Substantial evidence indicates that PrP^Sc is identical with the infectious agent or comprises at least an indispensable part thereof. Irrespective of its exact physical nature, in this article the term ‘prion’ is used to refer to the infectious agent causing spongiform encephalopathies [3].

The prion hypothesis was put forward by S. Prusiner. In its simplest form it states that the prion is devoid of any informational nucleic acids [35] and consists solely of PrP^Sc. Interaction of PrP^Sc with the normal host protein, PrP^C, forces PrP^C to adopt the conformation of PrP^Sc, resulting in an amplification of the infectious agent. The fact that the infectious agent is largely resistant to heat and irradiation speaks strongly in favor of the protein only hypothesis. Additional evidence is provided by recent findings demonstrating that mouse PrP^C expressed in both yeast and neuronal tumor cells can be converted into an abnormal form similar to that adopted by naturally occurring mouse PrP^Sc. Transgenic mice overexpressing mutated prion protein develop some TSE features, yet essential criteria of prions (including crucially, transmissibility) are not fulfilled by these transgenetically produced prion proteins. In addition, the possibility was raised that the observed neurodegeneration may be due to other factors since similar transgenic mice yielded different results [28]. Although the conversion of PrP^C to a PrP^Sc-like protein has been possible under cell culture conditions, the ultimate proof of the prion hypothesis, that is the de novo generation of infectious PrP^Sc has not been possible [26].

On the other hand, skeptics of the protein-only hypothesis argue that the failure of ionizing irradiation to destroy the infectious properties of the agent does not disprove a viral hypothesis. The possibility that the infectious agent includes a nucleic acid, for which PrP^C serves as a receptor or packaging signal cannot be excluded [10]. In fact viruses with small (2–4 kb) genomes, and some retroviruses, are known to resist ionizing irradiation [36].

Section snippets

Common features of prion diseases

Primary symptoms of TSEs in humans are progressive dementia and ataxia. Depending on the kind of human TSE, either one of these symptoms can be observed as the initial symptom. In the new variant of CJD, the initial symptoms are usually personality changes and psychosis.

The clinical symptoms that can be observed in higher mammals such as cows or sheep are similar in character. Disturbances in social behavior or inadequate reaction to acoustic or tactile stimuli are described as early symptoms

Human prion diseases

TSEs in humans can be divided into three groups: sporadic, genetic and iatrogenic disease. By far the most common TSE among humans is sporadic CJD with a world-wide incidence of 1–2 cases per 1 million per year. Sporadic CJD is not associated with any known mutation in the gene coding for the prion protein, termed PRNP. Although the pathological features of the disease have been known for a long time and the biochemical reactions leading to these pathological features have been studied

Diagnostic tools…

Clinically, patients suffering from CJD show a wide spectrum of diversely associated symptoms. The typical, rapidly progressive form includes dementia, myoclonus, cerebellar ataxia, visual disturbances and periodic electroencephalography. Yet other forms of the disease exist, and may give rise to diagnostic difficulties. Albeit not completely diagnostic, periodic sharp-wave complexes upon electroencephalography or 14-3-3 protein detection in spinal fluid are helpful for diagnosis, when clinical

Prion diseases affecting animals

A TSE affecting sheep, referred to as scrapie, has been known to exist for over 250 years. First reports of this disease date back to 1732 in England and 1759 in Germany. Nowadays scrapie is endemic in a number of countries. Other countries like New Zealand or Australia are considered scrapie-free [32]. The exact mode of transmission of scrapie is not known. Essentially the infectious agent could reach the host by oral uptake, through skin lesions or via an unaffected host. In addition to these

Prion neuroinvasion

The only organ system in which severe histopathological damage can be demonstrated as a consequence of infection with prions is the central nervous system. This applies to all human and animal TSEs. In certain TSEs, like BSE in cows or nvCJD and iatrogenic CJD in humans, the disease is caused by peripheral uptake of prion-infested material raising the question as to how prions find their way to the CNS. This process, referred to as neuroinvasion, can be simulated in mouse models by peripheral

Therapeutic approaches

Considering that the scale of the nvCJD epidemic cannot be estimated, with predicted nvCJD victims ranging from only a few hundred to many thousands, the need for therapeutic strategies tackling TSEs is obvious. However, development of anti-TSE drugs has been a difficult task because as expected standard antiviral and antibacterial approaches to these diseases did not show any effects.

Over the past 25 years, a variety of different classes of compounds have been tested as inhibitors of TSEs.

Outlook

Research in the TSE field has attained considerable progress in the last years. The number of new discoveries opening up insights into prion propagation and neuroinvasion has been tremendous. Still central issues like the true nature of the agent or the cause of the most common form of human prion diseases, sporadic CJD, are not fully understood yet.

The discovery of BSE cases outside of the UK and the possibility of transmission of nvCJD via blood or surgical material has put pressure on the

Acknowledgements

We thank M. Peltola and M. König for technical help. This work was supported by the Kanton of Zürich, the Bundesämter für Gesundheit, Veterinärwesen, Bildung und Wissenschaft, and by grants from the Swiss National Research Program NFP38/NFP38+ and of the companies Baxter and Migros.

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Review: A review on classical and atypical scrapie in caprine: Prion protein gene polymorphisms and their role in the disease
2016, Animal
Scrapie is a naturally occurring transmissible spongiform encephalopathy in sheep and goat. It has been known for ~250 years and is characterised by the accumulation of an abnormal isoform of a host-encoded prion protein that leads to progressive neurodegeneration and death. Scrapie is recognised in two forms, classical and atypical scrapie. The susceptibility to both types of scrapie is influenced by polymorphisms of the prion protein gene (PRNP). Sheep susceptibility or resistance to classical scrapie is strongly regulated by the polymorphisms at codons 136, 154 and 171 of the PRNP. The genetic role in atypical scrapie in sheep has been defined by polymorphisms at codons 141, 154 and 171, which are associated with different degrees of risk in the occurrence of the ovine disease. Progress has been achieved in the prevention of scrapie in sheep due to efficient genetic breeding programmes based on eradication and control of the disease. In Europe, the success of these programmes has been verified by applying eradication and genetic selection plans. In general terms, the ovine selection plans aim to eliminate and reduce the susceptible allele and to enrich the resistant allele ARR. During outbreaks all susceptible animals are slaughtered, only ARR/ARR resistant rams and sheep and semi-resistant females are preserved. In the occurrence of scrapie positive goats a complete cull of the flock (stamping out) is performed with great economic loss and severe risk of extinction for the endangered breeds. The ability to select scrapie-resistant animals allows to define new breeding strategies aimed to boost genetic progress while reducing costs during scrapie outbreaks. Allelic variants of PRNP can be protective for caprine scrapie, and the knowledge of their distribution in goats has become very important. Over the past few years, the integration of genetic information on goat populations could be used to make selection decisions, commonly referred to as genetic selection. The objective of this review was to summarise the main findings of polymorphisms of the caprine prion protein (PrP) gene and to discuss the possible application of goat breeding schemes integrating genetic selection, with their relative advantages and limitations.
PRNP polymorphisms in four Italian sheep breeds
2015, Livestock Science
Citation Excerpt :
Prion (from proteinaceous infectious only) diseases, also known as TSEs (Transmissible Spongiform Encephalopathies) are a unique group of illness because they are both inheritable and infectious (Glatzel and Aguzzi, 2001).
Prions are responsible for transmissible spongiform encephalopathies (TSEs), also called scrapie in sheep. Single nucleotide polymorphisms (SNPs) in PRNP have been shown to play a crucial role in terms of incubation period and/or susceptibility to scrapie. Considering codons 136, 154, 171, five main alleles, associated with different degrees of susceptibility to classical scrapie have been detected. Homozygous ARR sheep are resistant to scrapie infection, however this genotype is not so frequent in some breeds. VRQ and ARQ alleles on the other hand are associated with a high susceptibility to scrapie. Additional polymorphisms within the ARQ allele, have been associated with scrapie resistance. Therefore, it is important to assess the frequency of both main and minor allelic variants, in order to develop a breeding programme based on genetic selection that simultaneously, increases scrapie resistance, and maintains a high variability of PRNP. Allelic and genotypic PRNP frequencies, at the three main codons, were determined in four sheep breeds reared in central Italy (Appenninica, Bergamasca, Comisana and Sarda). Moreover homozygous ARQ sheep have been investigated to measure the frequencies of minor allelic variants. In this study the AT₁₁₂RQ and ARQK₁₇₆ protective allelic variants were detected. The AT₁₁₂RQ allele was observed (ranging from 6.3% to 31.8%) in all the analysed breeds with the exception of Sarda sheep. The ARQK₁₇₆ allele by contrast was observed only in Sarda breed (4.6%). Moreover five non synonymous polymorphisms were also found (Q101R, G127S, L141F, H143R, and H180Y).
The disintegrin ADAM9 indirectly contributes to the physiological processing of cellular prion by modulating ADAM10 activity
2005, Journal of Biological Chemistry
Citation Excerpt :
One of the most puzzling discoveries in recent neurobiology was the demonstration that a new type of neurodegenerative diseases, transmissible spongiform encephalopathies, could be caused by an infectious proteinaceous agent generically called prion (1). Interest in this type of pathology had been boosted by the observation that, besides well known cases reported for ovines (called scrapie) and later for bovines (bovine spongiform encephalopathies), some cases referred to as Creutzfeldt-Jakob Disease and, more recently, new variants of Creutzfeldt-Jakob Disease, could be found in human beings (3–5), revealing a new problem of public health. The “infectious” agent (PrPsc or PrPres) was found to occur as an “abnormal” conformer of a ubiquitous protein called PrPc and differs from the latter by its lower susceptibility to proteolysis (6, 7).
The cellular prion protein (PrP^c) is physiologically cleaved in the middle of its 106–126 amino acid neurotoxic region at the 110/111↓112 peptidyl bond, yielding an N-terminal fragment referred to as N1. We recently demonstrated that two disintegrins, namely ADAM10 and ADAM17 (TACE, tumor necrosis factor alpha converting enzyme) participated in both constitutive and protein kinase C-regulated generation of N1, respectively. These proteolytic events were strikingly reminiscent of those involved in the so-called “α-secretase pathway” that leads to the production of secreted sAPPα from βAPP. We show here, by transient and stable transfection analyses, that ADAM9 also participates in the constitutive secretion of N1 in HEK293 cells, TSM1 neurons, and mouse fibroblasts. Decreasing endogenous ADAM9 expression by an antisense approach drastically reduces both N1 and sAPPα recoveries. However, we establish that ADAM9 was unable to increase N1 and sAPPα productions after transient transfection in fibroblasts depleted of ADAM10. Accordingly, ADAM9 is unable to cleave a fluorimetric substrate of membrane-bound α-secretase activity in ADAM10^-/- fibroblasts. However, we establish that co-expression of ADAM9 and ADAM10 in ADAM10-deficient fibroblasts leads to enhanced membrane-bound and released fluorimetric substrate hydrolyzing activity when compared with that observed after ADAM10 cDNA transfection alone in ADAM10^-/- cells. Interestingly, we demonstrate that shedded ADAM10 displays the ability to cleave endogenous PrP^c in fibroblasts. Altogether, these data provide evidence that ADAM9 is an important regulator of the physiological processing of PrP^c and βAPP but that this enzyme acts indirectly, likely by contributing to the shedding of ADAM10. ADAM9 could therefore represent, besides ADAM10, another potential therapeutic target to enhance the breakdown of the 106–126 and Aβ toxic domains of the prion and βAPP proteins.
RNA mutagenesis and sporadic prion diseases
2004, Journal of Theoretical Biology
The extremely low incidence of sporadic prion diseases suggests that they may arise as a rare stochastic event in otherwise healthy animals or humans. Current hypotheses for sporadic prion disease include horizontal transmission, spontaneous conversion of Prp^C into Prp^Sc, and somatic mutation of the Prp gene. Here, we suggest RNA mutation as a possible initial event in the etiology of sporadic prion disease. The proposed model is based on (i) the fact that in Prp-expressing cells, mutations are statistically more likely to occur in the Prp mRNA population than in the corresponding two copies of the Prp gene, and (ii) the absence of RNA repair mechanisms analagous to those found for DNA mismatch correction resulting in a relatively higher rate of RNA mutations. Here, we suggest that translation of mutated Prp mRNA could lead to the synthesis of transient Prp^Sc which results in the conversion of Prp^C into Prp^Sc and the propagation of a disease-associated isoform. This model points to RNA mutation as a possible mechanism for the generation of sporadic prion diseases and other pathological disorders in which infectious proteins other than Prp^Sc might be implicated.
Prions and the Immune System: A Journey Through Gut, Spleen, and Nerves
2003, Advances in Immunology
Citation Excerpt :
While it has been known for a long time that specific strains of prions may preferentially affect specific subsets of neurons, the Blättler/Brown paradox may uncover an analogous phenomenon in peripheral prion pathogenesis. The latter question may be much more important than it may appear at face value, and its clarification may warrant the investment of significant resources, since the molecular and cellular basis of peripheral tropism of prion strains is likely to be directly linked to the potential danger of BSE in sheep (Glatzel and Aguzzi, 2001; Bruce et al., 2002; Kao et al., 2002), as well as the potential presence of vCJD prions in human blood (Aguzzi, 2000). As mentioned above, prion infectivity rises very rapidly (in a matter of days) in the spleen of intraperitoneally infected mice.
For more than two decades it has been contended that prion infection does not elicit immune responses: transmissible spongiform encephalopathies do not go along with conspicuous inflammatory infiltrates, and antibodies to the prion protein are typically undetectable. Why is it, then, that prions accumulate in lymphoid organs, and that various states of immune deficiency prevent peripheral prion infection? This review revisits the current evidence of the involvement of the immune system in prion diseases, while attempting to trace the elaborate mechanisms by which peripherally administered prions invade the brain and ultimately cause damage. The investigation of these questions leads to unexpected detours, including the neurophysiology of lymphoid organs, and even the function of a prion protein homolog in male fertility.
Alzheimer's and prion diseases: Distinct pathologies, common proteolytic denominators
2002, Trends in Neurosciences
Alzheimer's and prion pathologies are often seen as distinct neurodegenerative diseases, particularly because the infectious character of some prion-associated pathology makes this stand apart from classical neurodegenerative, age-related syndromes. Are there specific common denominators that could link the two diseases? It appears that βAPP (β-amyloid precursor protein) and PrP^c (cellular prion protein), the ‘guilty’ proteins involved in these pathologies, undergo protein-kinase-C-regulated proteolysis by identical proteases of the disintegrin family. This cleavage occurs in an analogous way, in the middle of the ‘toxic’ Aβ and PrP^c106–126 domains of βAPP and PrP^c, respectively. As these two sequences trigger similar caspase-dependent and -independent cascades, this proteolytic attack could be seen as an inactivating process aimed at clearing cells of these endogenous ‘toxins’ and, thus, preventing the associated proteinaceous accumulation usually detected in affected brains. It is our opinion that targeting these disintegrins with specific ‘activators’ could be a suitable strategy to slow down, or even arrest, βAPP and PrP^c-related aggregation and toxicity.

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ReviewThe shifting biology of prions

Abstract

Introduction

Section snippets

Common features of prion diseases

Human prion diseases

Diagnostic tools…

Prion diseases affecting animals

Prion neuroinvasion

Therapeutic approaches

Outlook

Acknowledgements

Lancet

Neuron

Lancet

Lancet

Between cows and monkeys

Nature

Prions: health scare and biological challenge

Nat. Rev. Mol. Cell Biol.

Prion research: the next frontiers

Nature

Transmission dynamics and epidemiology of BSE in British cattle

Nature

Nearly ubiquitous tissue distribution of the scrapie agent precursor protein

Neurology

Iatrogenic Creutzfeldt–Jakob disease at the millennium

Neurology

Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent

Nature

Neuropathological diagnostic criteria for Creutzfeldt–Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases)

Brain Pathol.

Inhibition of protease-resistant prion protein formation by porphyrins and phthalocyanines

Proc. Natl. Acad. Sci. USA

BSE and prions: uncertainties about the agent

Science

Prion protein transgenes and the neuropathology in prion diseases

Brain Pathol.

Pathogenesis of scrapie virus infection in the mouse

J. Infect. Dis.

Binding of disease-associated prion protein to plasminogen

Nature

Transmission of Creutzfeldt–Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery

J. Neurol. Neurosurg. Psychiatry

PrP(C) expression in the peripheral nervous system is a determinant of prion neuroinvasion

J. Gen. Virol.

The same prion strain causes vCJD and BSE

Nature

Review
The shifting biology of prions