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Pathogens
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PrPSc prions: state of the art
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PrPSc prions: state of the art

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (15 September 2017) | Viewed by 101263

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Joaquín Castilla

E-Mail Website
Guest Editor
1. CIC bioGUNE, Parque tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain
2. IKERBASQUE, Basque Foundation for Science, Bilbao 48011, Bizkaia, Spain
Interests: the molecular mechanisms involved in the prion transmission between different species
Dr. Jesús R. Requena

E-Mail Website1 Website2
Guest Editor
CIMUS Biomedical Research Institute, University of Santiago de Compostela-IDIS, Room SS1D, Avenida de Barcelona s/n, 15782 Santiago de Compostela, Spain
Interests: prion diseases; PrPSc; PrPSc structure

Special Issue Information

Dear Colleagues,

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of fatal and transmissible neurodegenerative disorders characterized by long incubation periods, misfolded prion protein (PrP) deposition, and, usually, spongiform vacuolation. These devastating diseases affect many mammals, with the best known examples being Creutzfeldt-Jakob disease (CJD), Fatal familial insomnia (FFI) or Kuru in humans, scrapie in sheep, Bovine spongiform encephalopathy (BSE) in cattle and Chronic wasting disease (CWD) in cervids. The nature of the causal agent has been highly controversial, although it is amply demonstrated and widely accepted now that it is an aberrantly folded prion protein (PrPSc), which transforms the normal cellular prion protein (PrPC) into an infectious and transmissible isoform. Prion diseases can be classified into three different types according to their origin, sporadic (putatively spontaneous), acquired or hereditary. Sporadic prion diseases are the result of an apparently spontaneous misfolding of PrPC in an individual and include sporadic Creutzfeldt-Jakob disease (sCJD), which represents 85–90% of all human prion diseases. There are other infrequent and recently discovered atypical forms of sporadic prion diseases like atypical scrapie in sheep and goats, sporadic Fatal Insomnia (sFI) and variable protease-sensitive prionopathy (VPSPr) in humans. The hereditary or familial forms are associated with a range of dominantly inherited mutations within the open reading frame (ORF) of the prion protein gene (PRNP). More than 30 different pathogenic mutations, which give rise to specific clinically manifested heritable phenotypes, have been described to date and include: genetic CJD (gCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS) and FFI. Finally, the infectious or acquired forms of the disease are due to accidental exposure to prion contaminated tissues and the best-known examples are variant CJD (vCJD) that affects humans that consumed BSE-contaminated products and iatrogenic CJD (iCJD) that arose in the recent past from prion contaminated surgical instruments or tissues from affected donors. Although the measures implemented after the mad-cow disease crisis have practically eliminate the risk of acquired prion diseases, there is no way to reduce sporadic cases, as they develop in an unpredictable way.

Despite major steps forward achieved in the last three decades of research on TSEs, there are still many unresolved key issues that hamper the development of effective therapies. The main remaining questions include the resolution of the three dimensional structure of infectious prions at the atomic level; clarifying the physiological role(s) of native PrPC, understanding the molecular mechanisms ruling the strain variability and interspecies transmission of TSEs, as well as the exact pathogenic mechanism in the course of a prion disorder. However, the last decade has been particularly prolific in advances in the prion field, so that shedding a definitive light on these issues now appears more feasible than ever. Among others, prion propagation in vitro has been achieved, leading to new diagnostic methods and also to the generation of infectious prions using bacterially expressed proteins; the basic architecture of infectious prions has been deciphered; new prion disease types have been described in humans and other animals and well known prion disorders have emerged in continents previously free of them, as it is the case of CWD in Europe. Yet, there is no therapy or treatment available for these fatal disorders, which is the ultimate goal for researchers working on this unusual pathogen.

In this exciting context, Pathogens will launch a Special Issue devoted to “PrPSc Prions: Towards the Final Frontier”. Although the title might seem redundant (“PrPSc prions”), it is now clear that “PrPSc” and “prion” are not synonyms. On the one hand, there are other prions, infectious proteins, in yeasts and fungi. Additionally, there are a number of proteins involved in human pathology that are strong candidates to being granted the status of prions. In particular, Aβ, tau, synuclein, although a very intense controversy exists and the issue is not still settled. This Special Issue will keep away from these other prions and potential prions and focus on PrPSc.

Both original research and review articles are welcomed. Potential topics include, but are not limited to:

  • Transmission barriers in prion diseases.
  • Pathogenic mechanisms in prion diseases.
  • Potential functions of PrPC.
  • Towards a definitive diagnosis in prion diseases.

Dr. Joaquín Castilla
Dr. Jesús R. Requena
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Prions
  • Prion diseases
  • Prion propagation
  • Prion structure
  • Scrapie
  • Bovine spongiform encephalopathy
  • BSE
  • Chronic wasting disease
  • CWD
  • Creutzfeldt-Jakob disease
  • Gerstmann-Sträussler-Scheinker disease
  • GSS
  • Variably protease-sensitive prionopathy
  • VPSPr
  • Therapeutics
  • Therapy

Published Papers (10 papers)

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14 pages, 782 KiB  
Review
Comparing the Folds of Prions and Other Pathogenic Amyloids
by José Miguel Flores-Fernández, Vineet Rathod and Holger Wille
Pathogens 2018, 7(2), 50; https://doi.org/10.3390/pathogens7020050 - 04 May 2018
Cited by 9 | Viewed by 6058
Abstract
Pathogenic amyloids are the main feature of several neurodegenerative disorders, such as Creutzfeldt–Jakob disease, Alzheimer’s disease, and Parkinson’s disease. High resolution structures of tau paired helical filaments (PHFs), amyloid-β(1-42) (Aβ(1-42)) fibrils, and α-synuclein fibrils were recently reported using cryo-electron microscopy. A high-resolution structure [...] Read more.
Pathogenic amyloids are the main feature of several neurodegenerative disorders, such as Creutzfeldt–Jakob disease, Alzheimer’s disease, and Parkinson’s disease. High resolution structures of tau paired helical filaments (PHFs), amyloid-β(1-42) (Aβ(1-42)) fibrils, and α-synuclein fibrils were recently reported using cryo-electron microscopy. A high-resolution structure for the infectious prion protein, PrPSc, is not yet available due to its insolubility and its propensity to aggregate, but cryo-electron microscopy, X-ray fiber diffraction, and other approaches have defined the overall architecture of PrPSc as a 4-rung β-solenoid. Thus, the structure of PrPSc must have a high similarity to that of the fungal prion HET-s, which is part of the fungal heterokaryon incompatibility system and contains a 2-rung β-solenoid. This review compares the structures of tau PHFs, Aβ(1-42), and α-synuclein fibrils, where the β-strands of each molecule stack on top of each other in a parallel in-register arrangement, with the β-solenoid folds of HET-s and PrPSc. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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16 pages, 918 KiB  
Review
Pharmacological Agents Targeting the Cellular Prion Protein
by Maria Letizia Barreca, Nunzio Iraci, Silvia Biggi, Violetta Cecchetti and Emiliano Biasini
Pathogens 2018, 7(1), 27; https://doi.org/10.3390/pathogens7010027 - 07 Mar 2018
Cited by 36 | Viewed by 6246
Abstract
Prion diseases are associated with the conversion of the cellular prion protein (PrPC), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrPSc) that accumulates [...] Read more.
Prion diseases are associated with the conversion of the cellular prion protein (PrPC), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrPSc) that accumulates in brain tissues of affected individuals. PrPSc is a self-catalytic protein assembly capable of recruiting native conformers of PrPC, and causing their rearrangement into new PrPSc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrPSc, and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrPSc might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrPC, the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrPC in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrPC, discussing pharmacological properties and therapeutic potentials of each chemical class. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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11 pages, 3347 KiB  
Review
The Structure of PrPSc Prions
by Holger Wille and Jesús R. Requena
Pathogens 2018, 7(1), 20; https://doi.org/10.3390/pathogens7010020 - 07 Feb 2018
Cited by 63 | Viewed by 19160
Abstract
PrPSc (scrapie isoform of the prion protein) prions are the infectious agent behind diseases such as Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (deer, elk, moose, and reindeer), as well as goat and sheep scrapie. [...] Read more.
PrPSc (scrapie isoform of the prion protein) prions are the infectious agent behind diseases such as Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (deer, elk, moose, and reindeer), as well as goat and sheep scrapie. PrPSc is an alternatively folded variant of the cellular prion protein, PrPC, which is a regular, GPI-anchored protein that is present on the cell surface of neurons and other cell types. While the structure of PrPC is well studied, the structure of PrPSc resisted high-resolution determination due to its general insolubility and propensity to aggregate. Cryo-electron microscopy, X-ray fiber diffraction, and a variety of other approaches defined the structure of PrPSc as a four-rung β-solenoid. A high-resolution structure of PrPSc still remains to be solved, but the four-rung β-solenoid architecture provides a molecular framework for the autocatalytic propagation mechanism that gives rise to the alternative conformation of PrPSc. Here, we summarize the current knowledge regarding the structure of PrPSc and speculate about the molecular conversion mechanisms that leads from PrPC to PrPSc. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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29 pages, 1808 KiB  
Review
Prion Strains and Transmission Barrier Phenomena
by Angélique Igel-Egalon, Vincent Béringue, Human Rezaei and Pierre Sibille
Pathogens 2018, 7(1), 5; https://doi.org/10.3390/pathogens7010005 - 01 Jan 2018
Cited by 24 | Viewed by 6915
Abstract
Several experimental evidences show that prions are non-conventional pathogens, which physical support consists only in proteins. This finding raised questions regarding the observed prion strain-to-strain variations and the species barrier that happened to be crossed with dramatic consequences on human health and veterinary [...] Read more.
Several experimental evidences show that prions are non-conventional pathogens, which physical support consists only in proteins. This finding raised questions regarding the observed prion strain-to-strain variations and the species barrier that happened to be crossed with dramatic consequences on human health and veterinary policies during the last 3 decades. This review presents a focus on a few advances in the field of prion structure and prion strains characterization: from the historical approaches that allowed the concept of prion strains to emerge, to the last results demonstrating that a prion strain may in fact be a combination of a few quasi species with subtle biophysical specificities. Then, we will focus on the current knowledge on the factors that impact species barrier strength and species barrier crossing. Finally, we present probable scenarios on how the interaction of strain properties with host characteristics may account for differential selection of new conformer variants and eventually species barrier crossing. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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309 KiB  
Review
Recombinant PrP and Its Contribution to Research on Transmissible Spongiform Encephalopathies
by Jorge M. Charco, Hasier Eraña, Vanessa Venegas, Sandra García-Martínez, Rafael López-Moreno, Ezequiel González-Miranda, Miguel Ángel Pérez-Castro and Joaquín Castilla
Pathogens 2017, 6(4), 67; https://doi.org/10.3390/pathogens6040067 - 14 Dec 2017
Cited by 5 | Viewed by 3967
Abstract
The misfolding of the cellular prion protein (PrPC) into the disease-associated isoform (PrPSc) and its accumulation as amyloid fibrils in the central nervous system is one of the central events in transmissible spongiform encephalopathies (TSEs). Due to the proteinaceous [...] Read more.
The misfolding of the cellular prion protein (PrPC) into the disease-associated isoform (PrPSc) and its accumulation as amyloid fibrils in the central nervous system is one of the central events in transmissible spongiform encephalopathies (TSEs). Due to the proteinaceous nature of the causal agent the molecular mechanisms of misfolding, interspecies transmission, neurotoxicity and strain phenomenon remain mostly ill-defined or unknown. Significant advances were made using in vivo and in cellula models, but the limitations of these, primarily due to their inherent complexity and the small amounts of PrPSc that can be obtained, gave rise to the necessity of new model systems. The production of recombinant PrP using E. coli and subsequent induction of misfolding to the aberrant isoform using different techniques paved the way for the development of cell-free systems that complement the previous models. The generation of the first infectious recombinant prion proteins with identical properties of brain-derived PrPSc increased the value of cell-free systems for research on TSEs. The versatility and ease of implementation of these models have made them invaluable for the study of the molecular mechanisms of prion formation and propagation, and have enabled improvements in diagnosis, high-throughput screening of putative anti-prion compounds and the design of novel therapeutic strategies. Here, we provide an overview of the resultant advances in the prion field due to the development of recombinant PrP and its use in cell-free systems. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
1922 KiB  
Review
What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings?
by Daniel Hughes and Mark Halliday
Pathogens 2017, 6(4), 63; https://doi.org/10.3390/pathogens6040063 - 01 Dec 2017
Cited by 15 | Viewed by 7146
Abstract
The prion diseases are a collection of fatal, transmissible neurodegenerative diseases that cause rapid onset dementia and ultimately death. Uniquely, the infectious agent is a misfolded form of the endogenous cellular prion protein, termed PrPSc. Despite the identity of the molecular [...] Read more.
The prion diseases are a collection of fatal, transmissible neurodegenerative diseases that cause rapid onset dementia and ultimately death. Uniquely, the infectious agent is a misfolded form of the endogenous cellular prion protein, termed PrPSc. Despite the identity of the molecular agent remaining the same, PrPSc can cause a range of diseases with hereditary, spontaneous or iatrogenic aetiologies. However, the link between PrPSc and toxicity is complex, with subclinical cases of prion disease discovered, and prion neurodegeneration without obvious PrPSc deposition. The toxic mechanisms by which PrPSc causes the extensive neuropathology are still poorly understood, although recent advances are beginning to unravel the molecular underpinnings, including oxidative stress, disruption of proteostasis and induction of the unfolded protein response. This review will discuss the diseases caused by PrPSc toxicity, the nature of the toxicity of PrPSc, and our current understanding of the downstream toxic signaling events triggered by the presence of PrPSc. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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1599 KiB  
Review
How do PrPSc Prions Spread between Host Species, and within Hosts?
by Neil A. Mabbott
Pathogens 2017, 6(4), 60; https://doi.org/10.3390/pathogens6040060 - 24 Nov 2017
Cited by 28 | Viewed by 13473
Abstract
Prion diseases are sub-acute neurodegenerative diseases that affect humans and some domestic and free-ranging animals. Infectious prion agents are considered to comprise solely of abnormally folded isoforms of the cellular prion protein known as PrPSc. Pathology during prion disease is restricted [...] Read more.
Prion diseases are sub-acute neurodegenerative diseases that affect humans and some domestic and free-ranging animals. Infectious prion agents are considered to comprise solely of abnormally folded isoforms of the cellular prion protein known as PrPSc. Pathology during prion disease is restricted to the central nervous system where it causes extensive neurodegeneration and ultimately leads to the death of the host. The first half of this review provides a thorough account of our understanding of the various ways in which PrPSc prions may spread between individuals within a population, both horizontally and vertically. Many natural prion diseases are acquired peripherally, such as by oral exposure, lesions to skin or mucous membranes, and possibly also via the nasal cavity. Following peripheral exposure, some prions accumulate to high levels within the secondary lymphoid organs as they make their journey from the site of infection to the brain, a process termed neuroinvasion. The replication of PrPSc prions within secondary lymphoid organs is important for their efficient spread to the brain. The second half of this review describes the key tissues, cells and molecules which are involved in the propagation of PrPSc prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain. This section also considers how additional factors such as inflammation and aging might influence prion disease susceptibility. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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638 KiB  
Review
The Role of the Mammalian Prion Protein in the Control of Sleep
by Amber Roguski and Andrew C. Gill
Pathogens 2017, 6(4), 58; https://doi.org/10.3390/pathogens6040058 - 17 Nov 2017
Cited by 9 | Viewed by 5506
Abstract
Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the “eponymous” fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. [...] Read more.
Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the “eponymous” fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. It is important to establish the role of the cellular prion protein (PrPC), the key molecule involved in prion pathogenesis, within the sleep-wake system in order to understand fully the mechanisms underlying its contribution to both healthy circadian rhythmicity and sleep dysfunction during disease. Although severe disruption to the circadian rhythm and melatonin release is evident during the pathogenic phases of some prion diseases, untangling whether PrPC plays a role in circadian rhythmicity, as suggested in mice deficient for PrPC expression, is challenging given the lack of basic experimental research. We provide a short review of the small amount of direct literature focused on the role of PrPC in melatonin and circadian rhythm regulation, as well as suggesting mechanisms by which PrPC might exert influence upon noradrenergic and dopaminergic signaling and melatonin synthesis. Future research in this area should focus upon isolating the points of dysfunction within the retino-pineal pathway and further investigate PrPC mediation of pinealocyte GPCR activity. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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1822 KiB  
Review
Evolution of Diagnostic Tests for Chronic Wasting Disease, a Naturally Occurring Prion Disease of Cervids
by Nicholas J. Haley and Jürgen A. Richt
Pathogens 2017, 6(3), 35; https://doi.org/10.3390/pathogens6030035 - 05 Aug 2017
Cited by 41 | Viewed by 25572
Abstract
Since chronic wasting disease (CWD) was first identified nearly 50 years ago in a captive mule deer herd in the Rocky Mountains of the United States, it has slowly spread across North America through the natural and anthropogenic movement of cervids and their [...] Read more.
Since chronic wasting disease (CWD) was first identified nearly 50 years ago in a captive mule deer herd in the Rocky Mountains of the United States, it has slowly spread across North America through the natural and anthropogenic movement of cervids and their carcasses. As the endemic areas have expanded, so has the need for rapid, sensitive, and cost effective diagnostic tests—especially those which take advantage of samples collected antemortem. Over the past two decades, strategies have evolved from the recognition of microscopic spongiform pathology and associated immunohistochemical staining of the misfolded prion protein to enzyme-linked immunoassays capable of detecting the abnormal prion conformer in postmortem samples. In a history that parallels the diagnosis of more conventional infectious agents, both qualitative and real-time amplification assays have recently been developed to detect minute quantities of misfolded prions in a range of biological and environmental samples. With these more sensitive and semi-quantitative approaches has come a greater understanding of the pathogenesis and epidemiology of this disease in the native host. Because the molecular pathogenesis of prion protein misfolding is broadly analogous to the misfolding of other pathogenic proteins, including Aβ and α-synuclein, efforts are currently underway to apply these in vitro amplification techniques towards the diagnosis of Alzheimer’s disease, Parkinson’s disease, and other proteinopathies. Chronic wasting disease—once a rare disease of Colorado mule deer—now represents one of the most prevalent prion diseases, and should serve as a model for the continued development and implementation of novel diagnostic strategies for protein misfolding disorders in the natural host. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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1371 KiB  
Perspective
The Evolutionary unZIPping of a Dimerization Motif—A Comparison of ZIP and PrP Architectures
by Jian Hu, Holger Wille and Gerold Schmitt-Ulms
Pathogens 2018, 7(1), 4; https://doi.org/10.3390/pathogens7010004 - 29 Dec 2017
Cited by 4 | Viewed by 5556
Abstract
The cellular prion protein, notorious for its causative role in a range of fatal neurodegenerative diseases, evolved from a Zrt-/Irt-like Protein (ZIP) zinc transporter approximately 500 million years ago. Whilst atomic structures for recombinant prion protein (PrP) from various species have been available [...] Read more.
The cellular prion protein, notorious for its causative role in a range of fatal neurodegenerative diseases, evolved from a Zrt-/Irt-like Protein (ZIP) zinc transporter approximately 500 million years ago. Whilst atomic structures for recombinant prion protein (PrP) from various species have been available for some time, and are believed to stand for the structure of PrPC, the first structure of a ZIP zinc transporter ectodomain was reported only recently. Here, we compare this ectodomain structure to structures of recombinant PrP. A shared feature of both is a membrane-adjacent helix-turn-helix fold that is coded by a separate exon in the respective ZIP transporters and is stabilized by a disulfide bridge. A ‘CPALL’ amino acid motif within this cysteine-flanked core domain appears to be critical for dimerization and has undergone stepwise regression in fish and mammalian prion proteins. These insights are intriguing in the context of repeated observations of PrP dimers. Other structural elements of ZIP transporters and PrP are discussed with a view to distilling shared versus divergent biological functions. Full article
(This article belongs to the Special Issue PrPSc prions: state of the art)
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