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Prpsc Prions State of the Art Sc PrP Prions State of the Art Edited by Joaquín Castilla and Jesús R. Requena Printed Edition of the Special Issue Published in Pathogens www.mdpi.com/journal/pathogens PrPSc Prions: State of the Art Sc PrP Prions: State of the Art Special Issue Editors Joaqu´ınCastilla Jes ´usR. Requena MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Joaqu´ın Castilla Jes us´ R. Requena CIC bioGUNE University of Santiago de Compostela Spain Spain Editorial Office MDPI St. Alban-Anlage 66 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Pathogens (ISSN 2076-0817) from 2017 to 2018 (available at: https://www.mdpi.com/journal/pathogens/ special issues/prions study) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-308-9 (Pbk) ISBN 978-3-03897-309-6 (PDF) Cover image courtesy of Jesus´ R. Requena and Joaqu´ın Castilla. Articles in this volume are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book taken as a whole is c 2018 MDPI, Basel, Switzerland, distributed under the terms and conditions of the Creative Commons license CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents About the Special Issue Editors ..................................... vii Preface to ”PrPSc Prions: State of the Art” ............................... ix Daniel Hughes and Mark Halliday What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings? Reprinted from: Pathogens 2017, 6, 63, doi: 10.3390/pathogens6040063 ............... 1 Maria Letizia Barreca, Nunzio Iraci, Silvia Biggi, Violetta Cecchetti and Emiliano Biasini Pharmacological Agents Targeting the Cellular Prion Protein Reprinted from: Pathogens 2018, 7, 27, doi: 10.3390/pathogens7010027 ............... 23 Jos´eMiguel Flores-Fern´andez,Vineet Rathod and Holger Wille Comparing the Folds of Prions and Other Pathogenic Amyloids Reprinted from: Pathogens 2018, 7, 50, doi: 10.3390/pathogens7020050 ............... 39 Nicholas J. Haley and J ¨urgenA. Richt Evolution of Diagnostic Tests for Chronic Wasting Disease, a Naturally Occurring Prion Disease of Cervids Reprinted from: Pathogens 2017, 6, 35, doi: 10.3390/pathogens6030035 ............... 53 Holger Wille and Jes ´usR. Requena The Structure of PrPSc Prions Reprinted from: Pathogens 2018, 7, 20, doi: 10.3390/pathogens7010020 ............... 75 Jian Hu, Holger Wille and Gerold Schmitt-Ulms The Evolutionary unZIPping of a Dimerization Motif—A Comparison of ZIP and PrP Architectures Reprinted from: Pathogens 2018, 7, 4, doi: 10.3390/pathogens7010004 ................ 86 Jorge M. Charco, Hasier Era na,˜ Vanessa Venegas, Sandra Garc´ıa-Mart´ınez, Rafael Lopez-Moreno,´ Ezequiel Gonz´alez-Miranda, Miguel Angel´ P´erez-Castro and Joaqu´ın Castilla Recombinant PrP and Its Contribution to Research on Transmissible Spongiform Encephalopathies Reprinted from: Pathogens 2017, 6, 67, doi: 10.3390/pathogens6040067 ............... 97 Neil A. Mabbott How do PrPSc Prions Spread between Host Species, and within Hosts? Reprinted from: Pathogens 2017, 6, 60, doi: 10.3390/pathogens6040060 ...............117 Amber Roguski and Andrew C. Gill The Role of the Mammalian Prion Protein in the Control of Sleep Reprinted from: Pathogens 2017, 6, 58, doi: 10.3390/pathogens6040058 ...............158 Ang´eliqueIgel-Egalon, Vincent B´eringue,Human Rezaei and Pierre Sibille Prion Strains and Transmission Barrier Phenomena Reprinted from: Pathogens 2018, 7, 5, doi: 10.3390/pathogens7010005 ................170 v About the Special Issue Editors Joaqu´ın Castilla, Ph.D., obtained his Ph.D at the Autonomous University of Madrid. His expertise since 1998 is based on in vitro and in vivo replication of prions. In particular, his group studies the strain and species barrier phenomena in a cell-free system, trying to dissect the molecular mechanisms by which prions propagate and focusing on new anti-prion therapeutic approaches. His main achievements are: (i) the development of the most sensitive method for prion detection; (ii) generation of prion infectivity in a test tube, contributing to validation of the protein-only hypothesis; (iii) prion detection in blood for the first time in pre-symptomatic and symptomatic animals; (iv) confirmation that the in vitro prion propagation faithfully mimicks the three major phenomena governing transmissible spongiform diseases: infectivity, strain phenomenon and transmission barrier; and (v) establishing a reliable in vitro method for generating a diversity of recombinant prions with an invaluable value to understand the structure and other keys in the prion field. Jes´ us R. Requena, Ph.D., obtained his Ph.D. at the University of Santiago de Compostela. He conducted postdoctoral research on the role of post-translational modification of proteins in disease and ageing at the University of South Carolina, with John Baynes, and at the Protein Biochemistry Lab, NHLBI, NIH, with Earl Stadtman and Rod Levine. There, he started to work on the biochemistry Sc of prions and has since devoted his research activities to trying to understand the structure of PrP , which he believes holds the key to understanding how prions propagate. Recently, in collaboration with Holger Wille and Howard Young from the University of ASlberta, he has revealed the basic Sc architecture of PrP which conforms to a 4-rung beta-solenoid, using cryo-electron microscopy. In May, 2018, he chaired the Prion 2018 conference in Santiago de Compostela. vii Sc Preface to ”PrP Prions: State of the Art” Prions were defined by Stanley Prusiner, in 1982, as ”proteinaceous infectious particles” and more recently redefined as ”alternative protein conformations that exhibit self-propagation” (Watts & Prusiner, Cold Spring Harb. Perspect. Med. 2018; 8:a023507). The scrapie isoform of the prion protein, PrPSc, was the first prion to be identified. Identification of several fungal and yeast prions followed. More recently, a strong debate has erupted about whether Aβ, tau, alpha-synuclein, and other amyloids that propagate throughout the brain through templating mechanisms are prions too. From a purely biochemical point of view it seems that they are. However, the fact that only the PrPSc prion is known to date to have caused epidemic and epizootic events puts it in a unique position within biology. In this special issue of Pathogens, a number of reviews summarize the state of the art of our knowledge of PrPSc prions. Reviews are presented on what we know about their structure and propagation, the basis of strains and transmission barriers, the mechanisms of PrPSc toxicity, the possible function of PrPSc’s properly folded precursor, PrPC and its evolutionary history, and recent technical breakthroughs in diagnostics and therapy development, among other key aspects of PrPSc prion biology. Joaqu´ınCastilla, Jes ´usR. Requena Special Issue Editors ix pathogens Review What Is Our Current Understanding of PrPSc-Associated Neurotoxicity and Its Molecular Underpinnings? Daniel Hughes 1 and Mark Halliday 2,* 1 MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK; [email protected] 2 Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK * Correspondence: [email protected]; Tel.: +44-(0)122-376-2116 Received: 29 September 2017; Accepted: 27 November 2017; Published: 1 December 2017 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 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. Keywords: prion disease; neurodegeneration; neurotoxicity; proteostasis; PrPSc 1. Introduction The Prion diseases, or transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases characterized by extensive neuronal death, spongiform change and gliosis. Uniquely among neurodegenerative disease, the prion diseases are transmissible, with infection between members of the same species, and in some cases between different species, possible. Since the discovery that the infectious component of prions is comprised solely of protein, more specifically a misfolded
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