Vaccination with Prion Peptide-Displaying Polyomavirus-Like Particles Prolongs Incubation Time in Scrapie-Infected Mice
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Tätigkeitsbericht 2007/2008
Tätigkeitsbericht 2007/2008 8 200 / 7 0 20 Tätigkeitsbericht Stiftung bürgerlichen Rechts Martinistraße 52 · 20251 Hamburg Tel.: +49 (0) 40 480 51-0 · Fax: +49 (0) 40 480 51-103 [email protected] · www.hpi-hamburg.de Impressum Verantwortlich Prof. Dr. Thomas Dobner für den Inhalt Dr. Heinrich Hohenberg Redaktion Dr. Angela Homfeld Dr. Nicole Nolting Grafik & Layout AlsterWerk MedienService GmbH Hamburg Druck Hartung Druck + Medien GmbH Hamburg Titelbild Neu gestaltete Fassade des Seuchenlaborgebäudes Tätigkeitsbericht 2007/2008 Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg Martinistraße 52 · 20251 Hamburg Postfach 201652 · 20206 Hamburg Telefon: +49-40/4 80 51-0 Telefax: +49-40/4 80 51-103 E-Mail: [email protected] Internet: www.hpi-hamburg.de Das Heinrich-Pette-Institut ist Mitglied der Leibniz-Gemeinschaft (WGL) Internet: www.wgl.de Inhaltsverzeichnis Allgemeiner Überblick Vorwort ................................................................................................... 1 Die Struktur des Heinrich-Pette-Instituts .............................................. 2 Modernisierung des HPI erfolgreich abgeschlossen ............................ 4 60 Jahre HPI .............................................................................................. 5 Offen für den Dialog .............................................................................. 6 Preisverleihungen und Ehrungen .......................................................... 8 Personelle Veränderungen in -
Zinc and Copper Ions Differentially Regulate Prion-Like Phase
viruses Article Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates Anne Monette 1,* and Andrew J. Mouland 1,2,* 1 Lady Davis Institute at the Jewish General Hospital, Montréal, QC H3T 1E2, Canada 2 Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada * Correspondence: [email protected] (A.M.); [email protected] (A.J.M.) Received: 2 September 2020; Accepted: 12 October 2020; Published: 18 October 2020 Abstract: Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. -
Prion Diseases in Knock-In Mice Carrying Single Prp Codon Substitutions Associated with Human Diseases
Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases Walker S. Jacksona,b,c,1, Andrew W. Borkowskia,b,c, Nicki E. Watsona, Oliver D. Kingd, Henryk Faase, Alan Jasanoffe,f, and Susan Lindquista,b,c,2 aWhitehead Institute for Biomedical Research, Cambridge, MA 02142; bHoward Hughes Medical Institute, cDepartment of Biology, and fDepartments of Biological Engineering, Brain and Cognitive Sciences, and Nuclear Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; dDepartment of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655; and eFrances Bitter Magnet Laboratory, Cambridge, MA 02139 Contributed by Susan Lindquist, July 9, 2013 (sent for review March 7, 2013) In man, mutations in different regions of the prion protein (PrP) linked to it, provides an important general model for such are associated with infectious neurodegenerative diseases that investigations. have remarkably different clinical signs and neuropathological There are several types of human prion diseases, each begin- lesions. To explore the roots of this phenomenon, we created ning with pathologic processes in a different brain region and fi – a knock-in mouse model carrying the mutation associated with leading to distinct functional de cits: cognition [Creutzfeldt – – one of these diseases [Creutzfeldt–Jakob disease (CJD)] that was Jakob disease (CJD)], movement control (Gerstmann Sträussler Scheinker syndrome), or sleep and autonomic functions [fatal exactly analogous to a previous knock-in model of a different fl prion disease [fatal familial insomnia (FFI)]. Together with the familial insomnia (FFI)] (7). Prion diseases also af ict animals WT parent, this created an allelic series of three lines, each express- and include bovine spongiform encephalopathy (BSE) of cattle, scrapie of sheep and goats, and chronic wasting disease (CWD) ing the same protein with a single amino acid difference, and with of deer and elk (1). -
Mitochondrial Dysfunction in Preclinical Genetic Prion Disease: a Target for 7 Preventive Treatment?
1HXURELRORJ\RI'LVHDVH ² Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Mitochondrial dysfunction in preclinical genetic prion disease: A target for 7 preventive treatment? Guy Kellera,c,1, Orli Binyamina,c,1, Kati Frida,c, Ann Saadab,c, Ruth Gabizona,c,⁎ a Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Israel b Department of Genetics and Metabolic Diseases, The Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Israel c Medical School, The Hebrew University, Jerusalem, Israel ABSTRACT Mitochondrial malfunction is a common feature in advanced stages of neurodegenerative conditions, as is the case for the accumulation of aberrantly folded proteins, such as PrP in prion diseases. In this work, we investigated mitochondrial activity and expression of related factors vis a vis PrP accumulation at the subclinical stages of TgMHu2ME199K mice, modeling for genetic prion diseases. While these mice remain healthy until 5–6 months of age, they succumb to fatal disease at 12–14 months. We found that mitochondrial respiratory chain enzymatic activates and ATP/ROS production, were abnormally elevated in asymptomatic mice, concomitant with initial accumulation of disease related PrP. In parallel, the expression of Cytochrome c oxidase (COX) subunit IV isoform 1(Cox IV-1) was reduced and replaced by the activity of Cox IV isoform 2, which operates in oxidative neuronal conditions. At all stages of disease, Cox IV-1 was absent from cells accu- mulating disease related PrP, suggesting that PrP aggregates may directly compromise normal mitochondrial function. Administration of Nano-PSO, a brain targeted antioxidant, to TgMHu2ME199K mice, reversed functional and biochemical mitochondrial functions to normal conditions regardless of the presence of misfolded PrP. -
An Evolutionary Basis for Scrapie Disease : Identification of a Fish
72 Update TRENDS in Genetics Vol.19 No.2 February 2003 affect regulation of the human genome in a more global 11 Frith, M.C. et al. (2002) Statistical significance of clusters of motifs manner by creating S/MARs that form chromatin loops, represented by position specific scoring matrices in nucleotide and by shaping the sequence evolution of LCRs. sequences. Nucleic Acids Res. 30, 3214–3224 12 Wingender, E. et al. (2001) The TRANSFAC system on gene expression regulation. Nucleic Acids Res. 29, 281–283 Acknowledgements 13 Purucker, M. et al. (1990) Structure and function of the enhancer 30 to Galina V. Glazko was supported by research grants from NIH (GM-20293) the human A gamma globin gene. Nucleic Acids Res. 18, 7407–7415 and NASA (NCC2-1057) awarded to Masatoshi Nei. We thank Nathan 14 Li, Q. et al. (1999) Locus control regions: coming of age at a decade plus. J. Bowen and Wolfgang J. Miller for discussions on the relationship Trends Genet. 15, 403–408 between TEs and S/MARs. 15 Hardison, R. et al. (1997) Locus control regions of mammalian beta- globin gene clusters: combining phylogenetic analyses and exper- References imental results to gain functional insights. Gene 205, 73–94 1 The Human Genome Sequencing Consortium, (2001) Initial sequen- 16 Strausberg, R. et al. (1999) The mammalian gene collection. Science cing and analysis of the human genome. Nature 409, 860–921 286, 455–457 2 Kidwell, M.G. and Lisch, D.R. (2001) Perspective: transposable 17 Bode, J. et al. (1996) Scaffold/matrix-attached regions: topological elements, parasitic DNA, and genome evolution. -
Identification of a Novel Polyomavirus from Patients with Acute Respiratory Tract Infections Anne M
Washington University School of Medicine Digital Commons@Becker Open Access Publications 2007 Identification of a novel polyomavirus from patients with acute respiratory tract infections Anne M. Gaynor Washington University School of Medicine in St. Louis Michael D. Nissen Royal Children’s Hospital, Brisbane, Queensland, Australia David M. Whiley Royal Children’s Hospital, Brisbane, Queensland, Australia Ian M. Mackay Royal Children’s Hospital, Brisbane, Queensland, Australia Stephen B. Lambert Royal Children’s Hospital, Brisbane, Queensland, Australia See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Part of the Medicine and Health Sciences Commons Recommended Citation Gaynor, Anne M.; Nissen, Michael D.; Whiley, David M.; Mackay, Ian M.; Lambert, Stephen B.; Wu, Guang; Brennan, Daniel C.; Storch, Gregory A.; Sloots, Theo P.; and Wang, David, ,"Identification of a novel polyomavirus from patients with acute respiratory tract infections." PLoS Pathogens.,. e64. (2007). https://digitalcommons.wustl.edu/open_access_pubs/872 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Anne M. Gaynor, Michael D. Nissen, David M. Whiley, Ian M. Mackay, Stephen B. Lambert, Guang Wu, Daniel C. Brennan, Gregory A. Storch, Theo P. Sloots, and David Wang This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/872 Identification of a Novel Polyomavirus from Patients with Acute Respiratory Tract Infections Anne M. Gaynor1, Michael D. Nissen2, David M. -
Prion Disease Reporting and Investigation Guideline
Human Prion Diseases Transmissible spongiform encephalopathies (TSE) including Creutzfeldt - Jakob disease (CJD) Illness The causative agent is thought to be a misfolded infectious isoform, called PrPSc, of a normally occurring cellular protein, PrPC. The abnormal folding can occur spontaneously (sporadic), by genetic mutations (familial), or by the uptake of prions from an external source (iatrogenic, variant). Accumulation of PrPSc in the central nervous system causes progressive neurodegenerative spongiform changes. An average of 12 cases occur in Washington annually. No cases of variant CJD have been reported in Washington state to date. Signs and In sporadic cases: rapidly progressive dementia, visual disturbances, cerebellar dysfunction, Symptoms pyramidal and extra pyramidal dysfunction, and myoclonus. In variant cases: behavioral changes (psychosis, depression), painful sensory symptoms, and delayed neurologic signs. See Appendix A Incubation Variable, but very long; in the order of years to decades. Case Please see https://www.cdc.gov/prions/cjd/diagnostic-criteria.html for sporadic, familial, and Classification iatrogenic CJD and https://www.cdc.gov/prions/vcjd/diagnostic-criteria.html for variant CJD. Report all definite, probable and possible cases to CDE Differential Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, corticobasal diagnosis degeneration, progressive supranuclear palsy, neoplasms, viral encephalitis, metal toxicity Treatment Always fatal; death usually occurs within a year after onset of illness. Treatment is supportive. Laboratory/ Confirmatory testing requires pathologic examination of brain tissue. Pathologic and CSF testing Imaging are performed only at the National Prion Disease Pathology Surveillance Center (NPDPSC). See NPDPSC website for collection and shipment details. Tests for prion diseases are not performed at Public Health Laboratories (PHL). -
Lecture 1: INTRODUCTION in MEDICAL BIOLOGY. CELL STRUCTURE
Lecture 1: INTRODUCTION IN MEDICAL BIOLOGY. CELL STRUCTURE 1. Biology: The Science of Our Lives 2. Theories Contributing to Modern Biology: Cell Theory 3. Forms and Diversity of Life 4. Levels of Organization 5. Cell Structure Biology (from Greek βίος - life and λόγος - word, judgement) – is a branch of the natural sciences, and is the study of living organisms and their interactions with environment. The term was specially proposed by French naturalist Jean-Baptiste Pierre Antoine de Monet, Chevalier de Lamarck in 1802 Biology deals with every aspect of life in a living organism. Biology examines the structure, function, growth, origin, evolution, and distribution of living things. Modern biology is complex of sciences. Most biological sciences are specialized disciplines: Botany, Zoology, Protozoology, Microbiology, Virology, Molecular biology, Genetics, Embryology, Evolution theory, Ecology and so on. The history of biology traces the study of the living world from ancient to modern times. Although the concept of biology as a single coherent field arose in the 19th century, the biological sciences emerged from traditions of medicine and natural history reaching back to ancient Egyptian medicine and the works of Aristotle and Galen in the ancient Greco-Roman world, which were then further developed in the Middle Ages by Muslim physicians and scholars such as al-Jahiz, Avicenna, Avenzoar, Ibn al-Baitar and Ibn al-Nafis. Ancient Greek philosopher, Aristotle developed his Scala Naturae, or Ladder of Life, to explain his concept of the advancement -
Recent Developments in Studying Human Polyomaviruses
Journal of General Virology (2013), 94, 482–496 DOI 10.1099/vir.0.048462-0 Review From Stockholm to Malawi: recent developments in studying human polyomaviruses Mariet C. W. Feltkamp,1 Siamaque Kazem,1 Els van der Meijden,1 Chris Lauber1 and Alexander E. Gorbalenya1,2 Correspondence 1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands Mariet Feltkamp 2Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, [email protected] 119899 Moscow, Russia Until a few years ago the polyomavirus family (Polyomaviridae) included a dozen viruses identified in avian and mammalian hosts. Two of these, the JC and BK-polyomaviruses isolated a long time ago, are known to infect humans and cause severe illness in immunocompromised hosts. Since 2007 an unprecedented number of eight novel polyomaviruses were discovered in humans. Among them are the KI- and WU-polyomaviruses identified in respiratory samples, the Merkel cell polyomavirus found in skin carcinomas and the polyomavirus associated with trichodysplasia spinulosa, a skin disease of transplant patients. Another four novel human polyomaviruses were identified, HPyV6, HPyV7, HPyV9 and the Malawi polyomavirus, so far not associated with any disease. In the same period several novel mammalian polyomaviruses were described. This review summarizes the recent developments in studying the novel human polyomaviruses, and touches upon several aspects of polyomavirus virology, pathogenicity, epidemiology and phylogeny. Introduction polyomaviruses were identified in rodents, cattle and birds, but not in humans until this century. The polyomaviruses have been recognized as a separate virus family (Polyomaviridae) consisting of several species From 2005 on, eight novel human polyomaviruses (HPyV) since 1999. -
Micrornas in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine
cells Review MicroRNAs in Prion Diseases—From Molecular Mechanisms to Insights in Translational Medicine Danyel Fernandes Contiliani 1,2, Yasmin de Araújo Ribeiro 1,2, Vitor Nolasco de Moraes 1,2 and Tiago Campos Pereira 1,2,* 1 Graduate Program of Genetics, Department of Genetics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, Ribeirao Preto 3900, Brazil; [email protected] (D.F.C.); [email protected] (Y.d.A.R.); [email protected] (V.N.d.M.) 2 Department of Biology, Faculty of Philosophy, Sciences and Letters, University of Sao Paulo, Av. Bandeirantes, Ribeirao Preto 3900, Brazil * Correspondence: [email protected]; Tel.: +55-16-3315-3818 Abstract: MicroRNAs (miRNAs) are small non-coding RNA molecules able to post-transcriptionally regulate gene expression via base-pairing with partially complementary sequences of target tran- scripts. Prion diseases comprise a singular group of neurodegenerative conditions caused by endoge- nous, misfolded pathogenic (prion) proteins, associated with molecular aggregates. In humans, classical prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann– Sträussler–Scheinker syndrome, and kuru. The aim of this review is to present the connections between miRNAs and prions, exploring how the interaction of both molecular actors may help understand the susceptibility, onset, progression, and pathological findings typical of such disorders, as well as the interface with some prion-like disorders, such as Alzheimer’s. Additionally, due to the inter-regulation of prions and miRNAs in health and disease, potential biomarkers for non-invasive miRNA-based diagnostics, as well as possible miRNA-based therapies to restore the levels of dereg- Citation: Contiliani, D.F.; Ribeiro, Y.d.A.; de Moraes, V.N.; Pereira, T.C. -
The Mirna World of Polyomaviruses Ole Lagatie1*, Luc Tritsmans2 and Lieven J Stuyver1
Lagatie et al. Virology Journal 2013, 10:268 http://www.virologyj.com/content/10/1/268 REVIEW Open Access The miRNA world of polyomaviruses Ole Lagatie1*, Luc Tritsmans2 and Lieven J Stuyver1 Abstract Polyomaviruses are a family of non-enveloped DNA viruses infecting several species, including humans, primates, birds, rodents, bats, horse, cattle, raccoon and sea lion. They typically cause asymptomatic infection and establish latency but can be reactivated under certain conditions causing severe diseases. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in several cellular processes by binding to and inhibiting the translation of specific mRNA transcripts. In this review, we summarize the current knowledge of microRNAs involved in polyomavirus infection. We review in detail the different viral miRNAs that have been discovered and the role they play in controlling both host and viral protein expression. We also give an overview of the current understanding on how host miRNAs may function in controlling polyomavirus replication, immune evasion and pathogenesis. Keywords: Polyomaviruses, microRNAs, Virus-host interaction, Immune evasion Review for BKPyV, Merkel cell carcinoma (MCC) for Merkel General overview of polyomaviruses Cell Virus (MCPyV) and trichodysplasia spinulosa for Polyomaviruses comprise a family of DNA tumor vi- Trichodysplasia spinulosa-associated Polyomavirus (TSPyV) ruses. They are non-enveloped and have a circular, [4,10,11,14-20]. One of the most striking observations is the double stranded DNA genome of around 5,100 bp [1]. fact that asymptomatic infection occurs during childhood The virion consists of 72 pentamers of the capsid pro- which is followed ordinarily by life-long asymptomatic tein VP1 with a single copy of VP2 and VP3 associated persistence [21]. -
Introduction to Viroids and Prions
Harriet Wilson, Lecture Notes Bio. Sci. 4 - Microbiology Sierra College Introduction to Viroids and Prions Viroids – Viroids are plant pathogens made up of short, circular, single-stranded RNA molecules (usually around 246-375 bases in length) that are not surrounded by a protein coat. They have internal base-pairs that cause the formation of folded, three-dimensional, rod-like shapes. Viroids apparently do not code for any polypeptides (proteins), but do cause a variety of disease symptoms in plants. The mechanism for viroid replication is not thoroughly understood, but is apparently dependent on plant enzymes. Some evidence suggests they are related to introns, and that they may also infect animals. Disease processes may involve RNA-interference or activities similar to those involving mi-RNA. Prions – Prions are proteinaceous infectious particles, associated with a number of disease conditions such as Scrapie in sheep, Bovine Spongiform Encephalopathy (BSE) or Mad Cow Disease in cattle, Chronic Wasting Disease (CWD) in wild ungulates such as muledeer and elk, and diseases in humans including Creutzfeld-Jacob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), Alpers syndrome (in infants), Fatal Familial Insomnia (FFI) and Kuru. These diseases are characterized by loss of motor control, dementia, paralysis, wasting and eventually death. Prions can be transmitted through ingestion, tissue transplantation, and through the use of comtaminated surgical instruments, but can also be transmitted from one generation to the next genetically. This is because prion proteins are encoded by genes normally existing within the brain cells of various animals. Disease is caused by the conversion of normal cell proteins (glycoproteins) into prion proteins.