Mad Cow Disease and Related Spongiform Encephalopathies

223 Pages·2004·5.135 MB·English

by  J. R. Silveira, B. Caughey, G. S. Baron (auth.), Professor David A. Harris MD, PhD (eds.)

284
Current Topics
in Microbiology
and Immunology
Editors
R.W. Compans, Atlanta/Georgia
M.D. Cooper, Birmingham/Alabama
T. Honjo, Kyoto· H. Koprowski, Philadelphia/Pennsylvania
F. Melchers, Basel· M.B.A. Oldstone, La Jolla/California
S. Olsnes, Oslo· M. Potter, Bethesda/Maryland
P.K. Vogt, La Jolla/California· H. Wagner, Munich
Springer-Verlag Berlin Heidelberg GmbH
D. Harris (Ed.)
Mad Cow Disease
and Related
Spongifornt
Encephalopathies
With 34 Figures and 17 Tables
i
Springer
Professor David A. Harris, MD, PhD
Department of Cell Biology and Physiology
Washington University School of Medicine
660 South Euclid Ave
St. Louis, MO 63110
USA
e-mail: dharris@cellbio. wustl.edu
Cover illustration by M. Jeffrey and L. Gonzdlez showing disease specific PrP accumula
tion around a neuron in the brain of a BSE affected cow as revealed by the immuno
histochemical technique.
ISSN 0070-217X
ISBN 978-3-642-05756-4 ISBN 978-3-662-08441-0 (eBook)
DOI 10.1007/978-3-662-08441-0
Library of Congress Catalog Card Number 72-152360
This work is subject to copyright. All rights are reserved, whether the whole or part of the
material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data
banks. Duplication of this publication or parts thereof is permitted only under the provisions
of the German Copyright Law of September 9, 1965, in its current version, and permission for
use must always be obtained from Springer-Verlag Berlin Heidelberg GmbH.
Violations are liable for prosecution under the German Copyright Law.
springeronline.com
© Springer-Verlag Berlin Heidelberg 2004
Originally published by Springer-Verlag Berlin Heidelberg New York in 2004
So[tcover reprint of the hardcover 1st edition 2004
The use of general descriptive names, registered names, trademarks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from
the relevant protective laws and regulations and therefore free for general use.
Product liability: The publishers cannot quarantee that accuracy of any information about
dosage and application contained in this book. In every individual case the user must check
such information by consulting the relevant literature.
Cover design: design & production GmbH, Heidelberg
Typesetting: Stiirtz AG
Printed on acid-free paper - 27/3150 ag 5432 I 0
Preface
Bovine spongiform encephalopathy (BSE) has become the most publicly
recognizable example of a group of fatal neurodegenerative diseases
caused by prions. Prions are an unprecedented class of infectious particles
composed exclusively of protein without any associated nucleic acid. The
prototypical prion disease of animals is scrapie, which has been known for
over 200 years. Although prion disorders have long been of interest to the
scientific, medical, and veterinary communities, the emergence of the BSE
epidemic in the UK in the late 1980s and 1990s catapulted discussion of
these diseases onto the front pages of newspapers and into the halls of
government. The appearance of BSE in other European countries, Japan,
and most recently Canada, as well as the spread of chronic wasting disease
among deer and elk in North America, has intensified the need to under
stand and control these unusual disorders. The problem was moved force
fully into the realm of public health in 1996 with the emergence of variant
Creutzfeldt-Jakob disease (vCJD), a human form of BSE. Whether the
number of vCJD cases, presently less than 200, will increase further in the
coming years, or whether the epidemic will be self-limited remains to be
seen.
In this volume, leading authorities review key facets of BSE and related
spongiform encephalopathies of animals and humans. The subjects that
are covered include the molecular features of prions, the scope of the BSE
epidemic in France, the pathogenesis of BSE and scrapie, international mo
nitoring of BSE, vCJD (clinical, pathological, molecular, and epidemiologi
cal aspects), and chronic wasting disease of cervids. The work presented in
these chapters provides an essential background for understanding a
group of emerging infectious diseases that have come to assume a promi
nent place among both specialists and the public at large.
List of Contents
Prion Protein and the Molecular Features
of Transmissible Spongiform Encephalopathy Agents
J.R. Silveira, B. Caughey, and G.S. Baron ......... . . . . . . . . . . . . . . . 1
Past, Present and Future of Bovine Spongiform Encephalopathy
in France
D. Calavas, C. Ducrot, and T.G.M. Baron. . . . . . . . . . . . . . . . . . . . . . . . 51
Pathology and Pathogenesis
of Bovine Spongiform Encephalopathy and Scrapie
M. Jeffrey and 1. Gonzalez. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 65
Public Health and the BSE Epidemic
M.N. Ricketts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Clinical Features of Variant Creutzfeldt-Jakob Disease
R.G. Will and H.J.T. Ward. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 121
Neuropathology and Molecular Biology
of Variant Creutzfeldt- Jakob Disease
J.w. Ironside and M.W. Head. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 133
The Epidemiology of Variant Creutzfeldt-Jakob Disease
P.G. Smith, S.N. Cousens, J.N. Huillard d'Aignaux, H.J.T. Ward,
and R.G. Will. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 161
Chronic Wasting Disease of Cervids
M.W. Miller and E.S. Williams. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 193
Subject Index ............................................. 215
List of Contributors
(Their addresses can be found at the beginning of their respective chapters.)
Baron, G.S. 1 Ironside, J.w. 133
Baron, T.G.M. 51 Jeffrey, M. 65
Caughey, B. 1 Miller, M.W. 193
Calavas, D. 51 Ricketts, M.N. 99
Cousens, S.N. 161 Silveira, J.R. 1
Ducrot, C. 51 Smith, P.G. 161
Gonzalez, L. 65 Ward, H.J.T. 121, 161
Head, M.W. 133 Will, R.G. 121, 161
Huillard d'Aignaux, J.N. 161 Williams, E.S. 193
Prion Protein and the Molecular Features
of Transmissible Spongiform Encephalopathy
Agents
J. R. Silveira· B. Caughey· G. S. Baron
Laboratory of Persistent Viral Diseases, NIAID, NIH, Rocky Mountain Laboratories,
903 S. 4th St., Hamilton, MT 59840, USA
E-mail: [email protected]
Introduction . . . . . . . . . . 2
1.1 Nature of the TSE Agent .... 3
1.2 Nomenclature of PrP Isoforms 3
1.3 PrP Protein .......... . 4
1.4 PrP Polymorphisms in Bovine and Cervid Species 5
1.5 Normal Function of Prpe ........ . 7
2 TSE Disease-Associated Changes in PrP . 7
2.1 Folding and Unfolding of Prpres ..... . 8
2.2 Formation of Prpres by Deleted Forms of PrP 11
2.3 Structural Diversity in Abnormal TSE-Associated PrP Molecules 12
3 Potential Mechanisms of Prpres Formation ... 13
4 Specific Binding of Prpsen to Prpres Aggregates. 15
5 Prpres-Induced Conversion of Prpsen to Prpres 16
5.1 Biological Connections ............ . 18
6 Mechanistic Insights from Cell-Free Reactions 19
6.1 Role of the Disulfide Bond. . . . . . . . . . . . 20
6.2 Sites ofInteraction Between Prpsen and Prpres . 21
6.3 Conversions with Membrane-Bound Prpsen 23
6.4 Role of Helix 1 Salt Bridges . . . . . . . . . . . 26
7 Species Barriers and Interactions Between Heterologous PrP Molecules 27
7.1 Relationship of Efficiencies of Conversion to Interspecies Transmission 28
7.2 BSE and CWD . . . . . . . . . . . . . . . . . . . . . . . 28
7.3 Binding vs. Conversion of Heterologous PrP Molecules. 31
8 TSE Strains . 32
9 Conclusions. 35
References. . . . . 35
2 J. R. Silveira et al.
Abstract Transmissible spongiform encephalopathy (TSE) diseases, or
prion diseases, are neurodegenerative diseases found in a number of
mammals, including man. Although they are generally rare, TSEs are al
ways fatal, and as of yet there are no practical therapeutic avenues to
slow the course of disease. The epidemic of bovine spongiform encepha
lopathy (BSE) in the UK greatly increased the awareness of TSE diseases.
Although it appears that BSE has not spread to North America, chronic
wasting disease (CWD), a TSE found in cervids, is causing significant
concern. Despite decades of investigation, the exact nature of the infec
tious agent of the TSEs is still controversial. Although many questions
remain, substantial efforts have been made to understand the molecular
features of TSE agents, with the hope of enhancing diagnosis and treat
ment of disease, as well as understanding the fundamental nature of the
infectious agent itself. This review summarizes the current understand
ing of these molecular features, focusing on the role of the prion protein
(Prpc) and its relationship to the disease-associated isoform (PrPSC).
1
Introduction
Transmissible spongiform encephalopathy (TSE) diseases, or prion dis
eases, are neurodegenerative diseases found in a number of mammals,
including man. Although they are generally rare, TSEs are always fatal,
and as of yet there are no practical therapeutic avenues to slow the
course of disease. In the late 1980s and early 1990s, a large outbreak of
bovine spongiform encephalopathy (BSE) in the UK greatly increased
the awareness of TSE diseases. Since then, nearly 180,000 cases have
been confirmed in the UK (DEFRA BSE information General statistics
GB), and 129 people have died due to a new form of human TSE, termed
new variant Creutzfeldt-Jakob disease (vCJD) (UK Monthly CJD statis
tics). Data suggest that these occurrences are causally linked to BSE
(Bruce et al. 1997; Hill et al. 1997). Although it appears that BSE has not
spread to North America, chronic wasting disease (CWD), a TSE found
in cervids, is causing significant concern (for a review see Williams and
Miller 2002). No cases of human disease have been causally associated
with CWD (Belay et al. 2001), but it is too early to conclude that humans
are resistant to CWD. Furthermore, the presence of CWD in wild rumi
nants that exist on the same range as domestic livestock evokes ques
tions about the potential transmission of CWD between these species,
Prion Protein and the Molecular Features of Transmissible Spongiform 3
and the generation of new strains that might be hazardous to humans.
Although many questions remain, substantial efforts have been made in
understanding the molecular features of TSE agents, with the hope of en
hancing diagnosis and treatment of disease, as well as understanding the
fundamental nature of the infectious agent itself.
1.1
Nature of the TSE Agent
Early genetic studies in mice found that the Sine gene was important in
host susceptibility to TSEs (Dickinson et al. 1968). Subsequent work re
vealed that Sine coded for the prion (PrP) protein, a host-derived pro
tein often found accumulating in an abnormal, protease-resistant form
in the central nervous system and lymphoreticular tissues during TSE
disease. Substantial evidence now suggests that abnormal forms of PrP
are involved in the transmission and pathogenesis of TSE disease (for a
review see Chesebro 1999), and the prion hypothesis proposes that an
abnormal form of PrP is in fact the TSE infectious agent (Prusiner
1998). Strong support for the importance of PrP in TSEs is derived from
infectivity experiments performed with PrP knockout mice. These mice
appear to be completely protected against TSE disease, and their ability
to propagate infectivity was eliminated (Bueler et al. 1993). Nevertheless,
the exact nature of the TSE agent remains to be determined as discussed
below.
1.2
Nomenclature of PrP Isoforms
The accumulation of a number of designations for the various isoforms
of PrP in the TSE literature has compounded the challenge of under
standing these peculiar infectious agents. To simplify these designations
as best we can, we will use the term Prpc to refer to PrP in its normal
structure and conformation and the term Prpsen to refer generically to
protease-sensitive forms of PrP, whether normal (i.e., PrPC) or not (e.g.,
various recombinant forms). The terms Prpsc, PrpCJD, PrpBSE, etc., refer
to abnormal forms of PrP associated with the particular TSE disease,
and depending on the individual usage, may variably imply one or more
of the following properties: infectiousness, pathogenicity, protease resis
tance or a specific conformational state. More generically and opera-