DOCSLIB.ORG

Insight Into Prion Diseases: Structural Lessons Learned from Fungus

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Insight Into Prion Diseases: Structural Lessons Learned from Fungus Prions Gone Mad Insight into prion diseases: structural lessons learned from fungus Laconia SMART Team: Laura Block, Kea Schmuhl, Erin Cunningham, Tyler Foote, Ashley Toll, Cole Tidemann, Ashley Garb, Dakota Moore Advisor: Jodie Garb, Laconia High School Mentor: Anita Manogaran, Ph.D., Marquette University Abstract Recent Developments in Prion Biology Prions in Fungi Prion diseases, including bovine spongiform encephalopathy (mad cow) and Prion diseases are associated with protein aggregates. The aggregates form [Het-s] is a prion found in the fungus of Podospora anserina that is caused by the Het- Creutzfeldt–Jakob disease in humans, are caused by a misfolded protein in the when the normal protein undergoes misfolding (Fig. 3). This misfolded s protein. During prion formation, the Het-s protein forms ribbon-like structures brain that has the ability to convert the normal protein to the misfolded form. protein has the ability to convert other normally folded proteins of the same (Fig. 4). These ribbons then give rise to small aggregates in the cell, which are Prions in the brain lead to the formation of aggregates of misfolded protein, which kind to the misfolded form. The misfolded proteins have the tendency to associated with the [Het-s] prion. Currently, the [Het-s] prion is of interest because it are thought to be infectious and toxic to the cell. Additionally, these aggregates stack themselves in a tight arrangement called an aggregate. In humans, the is thought to have a structure similar to that of the human Prp prion. are resistant to detergents or heat, and are difficult to destroy. While reliable Prpc protein is located in the brain. The misfolding of Prpc forms large structural studies of human prion proteins have been unsuccessful, the structure aggregates within the brain and is associated with CJD. Figure 5. The [Het-s] forms ribbon- of the [HET-s] prion in the fungus Podospora anserina has been solved. The HET-s like structures during prion protein misfolds and assembles into a higher order structure called a “solenoid,” a formation5. When Het-s protein tube of circular beta sheets. Laconia SMART (Students Modeling a Research Topic) fuses to the Green Fluorescent Team modeled the HET-s protein with 3D printing technology, illustrating its Protein, long ribbon-like structures solenoid structure. Each “turn” of the solenoid consists of 21 amino acids. A are formed during the initial stages pocket of hydrophobic (V244, L276, F286, W287), hydrophilic (Q240, E280), and of [Het-s] prion formation (bottom glycine amino acid side chains is thought to stabilize the solenoid structure. Since panel). These ribbons later give human prion proteins are thought to share a similar solenoid structure with HET-s, Balguerie, A., Dos Reis, S., Coulary-Salin, B., Chaignepain, S., Sabourin, M., Schmitter, J.M., and Saupe, S.J. (2004) The sequences appended to the amyloid core region of the HET-s prion protein determine higher-order aggregate rise to fluorescent aggregates. studying HET-s provides insight into the molecular structure of human prions, Figure 3. Prion protein aggregation. A normally folded prion protein (circles) organization in vivo. J Cell Sci. 117, 2610 . which could potentially lead to advances in treatment of prion-related diseases. undergoes misfolding (becomes a triangle). The misfolded protein is able to switch a normally folded protein to the misfolded prion form (as shown by the small arrows). The accumulation of misfolded proteins leads to the formation of aggregates, which create sponge-like holes when deposited in the brain. Prions in History Structure of the [Het-s] Prion In the past, infectious diseases have been associated with fungi, parasites, viruses, Crystal structures of the [Het-s] prion indicate that the prion has a solenoid and bacteria. In 1982, Dr. Stanley B. Prusiner suggested that prion diseases were structure, as described in Fig. 4, in which the beta sheets are “stacked”. caused by aggregating infectious proteins and won the Nobel Prize in 1997 for his Prion Aggregates Made of Beta Sheets Hydrophobic (V244, L276, F286, W287) and hydrophilic (Q240, E280) amino acids work1. Prion proteins are associated with Creuzfeldt-Jakob disease (CJD) in humans are thought to keep this spring-like structure stable. and bovine spongiform encephalopathy (BSE), also known as “mad cow” disease. The conversion of the normal protein to the misfolded form results in a Mad cow disease received wide publicity in the mid 1990’s after cattle were fed structural change. The misfolded protein is rich in beta sheets. This bone meal from prion infected sheep. The diseased cattle were then thought to secondary feature is thought to be necessary for the formation of the have entered the food supply for humans, causing an outbreak of CJD. The public aggregates. It has been proposed that the newly misfolded protein uses the outcry in response to the BSE and CJD outbreaks challenged practices on how beta sheet conformation to assemble into fibril like aggregates. nations raise and monitor meat products. In the United States, comprehensive changes resulted from a “mammalian-to-ruminant feed ban through its BSE inspection and BSE feed testing programs2.” Figure 1. Creutzfeldt-Jakob disease and C Image modified from A B http://eebweb.arizona.edu/faculty/ma age adjusted death rate. The number of sel/research/prion- people who have died from CJD each replication/index.html Figure 6. Physical models of the [Het-s] prion based on 2KJ3.pdb. Physical protein year (blue bars) has increased between Figure 4. Beta sheets stack into a solenoid. Using the beta sheets, the models were built using ZCorp 3D printing technology. Three different angles of the 1979 and 2008, although the rate of misfolded proteins stack together to create a solenoid structure, similar to a models are shown. Hydrophobic amino acids (varying shades of blue) and death among the population remains at coil in a spring. This solenoid structure generates the fibril appearance hydrophilic amino acids (varying shades of red) involved in solenoid stabilization can approximately 1 in a million3. common in prion aggregates. be seen in A and C. The beta sheet “stacks” within the solenoid are visible in B. "CJD (Creutzfeldt-Jakob Disease, Classic)." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 13 Dec. 2010. Web. 28 Feb. 2012. Study of Fungal Prions Prion Diseases Lead to Sponge-like Holes in Brain Morphology Conclusion Human prion aggregates are highly resistant to heat treatment and Patients with CJD experience symptoms that include detergents. Therefore, resistance to destructive techniques and potential for Since the outbreak of bovine spongiform encephalopathy in cows and Creuzfeldt- dementia, poor motor coordination, and memory loss. infectivity make human prions possibly dangerous to work with in the Jakob disease in humans during the mid 1990’s, scientists have strived to Progression of the disease is rapid and always fatal. laboratory. Instead, prions found in organisms dissimilar to humans are used. understand prions. Because of the infectious nature of the misfolded proteins, Prions found in fungus are also caused by an infectious protein and behave researchers have looked into the fungal prion of [Het-s]. Human prions are thought Figure 2. Normal versus classic CJD brain tissue. Cross similarly to their mammalian counterparts. Using fungal prions as a model to form solenoid structures similar to [Het-s]. Therefore, studying the [Het-s] prion sections of post-mortem brains of CJD patients show large allows researchers to gain insight into the molecular structure of human structure could potentially lead scientists to new insights in relation to human holes in the tissue4. This spongy appearance is the reason prions without risking infection. Researchers have focused on the particular prions. The study of fungal prions provide a better understanding of human prions, for its descriptive name, spongiform encephalopathy. fungal prion [Het-s] of Podospora anserina . and potentially lead to the development of new medicines for prion-related Genetic Science Learning Center. "The Mystery of diseases. Kuru." Learn.Genetics 28 February 2012 References 1. Prusiner, S.B. (1982). Science. 216, 136-144 2. Bovine Spongiform Encephalopathy, or Mad Cow Disease, Centers for Disease Control and Prevention. http://www.cdc.gov/ncidod/dvrd/bse/ 3. Creutzfeldt-Jakob Disease. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention A SMART Team project supported by the National Institutes of Health Science Education Partnership Award (NIH-SEPA 1R25RR022749) and an NIH CTSA Award (UL1RR031973). 4. The mystery of Kuru. Learn Genetics. Genetic Science Learning Center. University of Utah. http://learn.genetics.utah.edu/content/begin/dna/prions/kuru.html 5. Balguerie, A., et al (2004). J Cell Sci. 117, 2610 6. Van Melckebeke, H.et al (2010). J.Am.Chem.Soc. 132: 13765-13775 .
Load more

Recommended publications
  • 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/).
    [Show full text]
  • Vaccination with Prion Peptide-Displaying Polyomavirus-Like Particles Prolongs Incubation Time in Scrapie-Infected Mice
    viruses Article Vaccination with Prion Peptide-Displaying Polyomavirus-Like Particles Prolongs Incubation Time in Scrapie-Infected Mice Martin Eiden 1,* , Alma Gedvilaite 2 , Fabienne Leidel 1,3, Rainer G. Ulrich 1 and Martin H. Groschup 1 1 Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Südufer 10, 17493 Greifswald-Insel Riems, Germany; [email protected] (F.L.); rainer.ulrich@fli.de (R.G.U.); martin.groschup@fli.de (M.H.G.) 2 Life Sciences Center, Institute of Biotechnology, Vilnius University, Sauletekio˙ al. 7, LT-10257 Vilnius, Lithuania; [email protected] 3 Task Force Animal Diseases, Darmstadt Regional Administrative Council, Luisenplatz 2, 64283 Darmstadt, Germany * Correspondence: martin.eiden@fli.de Abstract: Prion diseases like scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle or Creutzfeldt–Jakob disease (CJD) in humans are fatal neurodegenerative diseases characterized by the conformational conversion of the normal, mainly α-helical cellular prion protein (PrPC) into the abnormal β-sheet rich infectious isoform PrPSc. Various therapeutic or prophylactic approaches have been conducted, but no approved therapeutic treatment is available so far. Immunisation against prions is hampered by the self-tolerance to PrPC in mammalian species. One strategy to avoid this tolerance is presenting PrP variants in virus-like particles (VLPs). Therefore, we vaccinated C57/BL6 mice with nine prion peptide variants presented by hamster polyomavirus capsid protein VP1/VP2-derived VLPs. Mice were subsequently challenged intraperitoneally with the murine RML Citation: Eiden, M.; Gedvilaite, A.; prion strain. Importantly, one group exhibited significantly increased mean survival time of 240 days Leidel, F.; Ulrich, R.G.; Groschup, M.H.
    [Show full text]
  • Podospora Anserina Bibliography N° 10 - Additions
    Fungal Genetics Reports Volume 50 Article 15 Podospora anserina bibliography n° 10 - Additions Robert Debuchy Université Paris-Sud Follow this and additional works at: https://newprairiepress.org/fgr This work is licensed under a Creative Commons Attribution-Share Alike 4.0 License. Recommended Citation Debuchy, R. (2003) "Podospora anserina bibliography n° 10 - Additions," Fungal Genetics Reports: Vol. 50, Article 15. https://doi.org/10.4148/1941-4765.1161 This Special Paper is brought to you for free and open access by New Prairie Press. It has been accepted for inclusion in Fungal Genetics Reports by an authorized administrator of New Prairie Press. For more information, please contact [email protected]. Podospora anserina bibliography n° 10 - Additions Abstract Podospora anserina is a coprophilous fungus growing on herbivore dung. It is a pseudohomothallic species in which ascus development results, as in Neurospora tetrasperma but through a different process, in the formation of four large ascospores containing nuclei of both mating types. This special paper is available in Fungal Genetics Reports: https://newprairiepress.org/fgr/vol50/iss1/15 Debuchy: Podospora anserina bibliography n° 10 - Additions Number 50, 2003 27 Podospora anserina bibliography n/ 10 - Additions Robert Debuchy, Institut de Génétique et Microbiologie UMR 8621, Bâtiment 400, Université Paris-Sud, 91405 Orsay cedex, France. Fungal Genet. Newsl. 50: 27-36. Podospora anserina is a coprophilous fungus growing on herbivore dung. It is a pseudohomothallic species in which ascus development results, as in Neurospora tetrasperma but through a different process, in the formation of four large ascospores containing nuclei of both mating types. These ascospores give self-fertile strains.
    [Show full text]
  • 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.
    [Show full text]
  • 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).
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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).
    [Show full text]
  • 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
    [Show full text]
  • Prions As Protein-Based Genetic Elements
    14 Aug 2002 14:0 AR AR168-MI56-28.tex AR168-MI56-28.sgm LaTeX2e(2002/01/18) P1: IBD 10.1146/annurev.micro.56.013002.100603 Annu. Rev. Microbiol. 2002. 56:703–41 doi: 10.1146/annurev.micro.56.013002.100603 Copyright c 2002 by Annual Reviews. All rights reserved First published online as a Review in Advance on July 15, 2002 PRIONS AS PROTEIN-BASED GENETIC ELEMENTS Susan M. Uptain1 and Susan Lindquist2 1Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois 60637; e-mail: [email protected] 2Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Biology, Nine Cambridge Center, Cambridge, Massachusetts 02142; e-mail: lindquist [email protected] Key Words Sup35, Ure2, HET-s, Rnq1, amyloid ■ Abstract Fungal prions are fascinating protein-based genetic elements. They alter cellular phenotypes through self-perpetuating changes in protein conformation and are cytoplasmically partitioned from mother cell to daughter. The four prions of Saccharomyces cerevisiae and Podospora anserina affect diverse biological pro- cesses: translational termination, nitrogen regulation, inducibility of other prions, and heterokaryon incompatibility. They share many attributes, including unusual genetic behaviors, that establish criteria to identify new prions. Indeed, other fungal traits that baffled microbiologists meet some of these criteria and might be caused by prions. Recent research has provided notable insight about how prions are induced and prop- agated and their many biological roles. The ability to become a prion appears to be evolutionarily conserved in two cases. [PSI+] provides a mechanism for genetic vari- ation and phenotypic diversity in response to changing environments.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]