Table Of ContentM. H. Groschup
H. A. Kretzschmar (eds.)
Prion Diseases
Diagnosis
and Pathogenesis
Springer-Verlag Wien GmbH
Dr. Martin H. Groschup
Institut für Immunologie,
Bundesforschungsanstalt für Viruskrankheiten der Tiere,
Tübingen, Germany
Prof. Dr. Hans A. Kretzschmar
Institut für Neuropathologie, Ludwig-Maximilians-Universität,
München, Germany
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Preface
More than fourteen years ago the first cases of bovine spongiform en
cephalopathy (BSE) were diagnosed in British cattle. In the course of a
large epidemic, almost a million animals were infected and the majority
were slaughtered in the preclinical stage. Thus the consumer was exposed to
BSE infectivity until effective sanitary measures were implemented in the
United Kingdom and elsewhere.
When the first cases of a new variant form of Creutzfeldt-lakob disease
(vClD) were diagnosed in March 1996, transmission of BSE to humans was
considered the most likely explanation because of its coincidence in time
and geographical distribution in Europe. In the meantime, mouse trans
mission experiments and the molecular analysis of pathological prion
protein deposited in the central nervous system of vClD victims clearly
support this hypothesis. Hence, BSE has been treated as a zoonotic disease
since 1996, and additional measures have been implemented to protect
consumer health.
A comprehensive understanding of prion diseases and their infectious
agents is crucial for risk assessment as regards both animals and man, as
well as for working out adequate control strategies. To further the com
munication of the current knowledge and the exchange of diagnostic
technologies in the scientific community, a symposium on the 'Character
ization and Diagnosis of Prion Diseases' was held from September 23-25,
1999 in Tiibingen, Germany. This symposium was supported by funds
made available by the EU Commission.
The overwhelming interest and the participation of more than 500
scientists from 26 countries at the symposium made it a success. Thirty
seven speakers were invited by the members of the Editorial Board
(A. Aguzzi, l. Collinge, D. Dormont, M.H. Groschup, H.A. Kretzschmar
and C. Weissmann) to give lectures on their most recent experimental re
sults. More than 170 posters were displayed. Sixteen posters were selected
for platform presentation.
In particular the following questions were addressed:
1. What are the key features of the pathogenesis of prion diseases in hu
mans and animals?
2. Which molecular mechanisms determine prion transmissibility across
species barriers?
vi Preface
3. What are the factors that influence susceptibility of the host species to
disease?
4. Which animal and in-vitro models are currently available for the detec
tion and quantification of prion infectivity?
5. Which diagnostic techniques allow the reliable investigation and confir-
mation of suspect cases in animals and humans?
6. What are the molecular and biological characteristics of prion strains?
In this volume, twenty-seven invited speakers comprehensively summarize
answers to these questions. Although this selection cannot reflect the
enormous spectrum and depth of prion research, it certainly illustrates the
current state of the art in the field.
Martin H. Groschup
Hans A. Kretzschmar
Contents
Pathogenesis oj Prion Diseases
Glatzel, M., Klein, M. A., Brandner, S., Aguzzi, A.: Prions: from
neurografts to neuroinvasion. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3
Brown, K. L., Stewart, K., Ritchie, D., Fraser, H., Morrison, W. I.,
Bruce, M. E.: Follicular dendritic cells in scrapie pathogenesis. . . . . . .. 13
Jeffrey, M., McGovern, G., Martin, S., Goodsir, C. M., Brown, K. L.:
Cellular and sub-cellular localisation of PrP in the lymphoreticular
system of mice and sheep . . . . . . . . . . . . . . . . . . . . . . . . .. .. . .2 3.
Beringue, V., Lamoury, F., Adjou, K. T., Maignien, T., Demoy, M.,
Couvreur, P., Dormont, D.: Pharmacological manipulation of early
Prpres accumulation in the spleen of scrapie-infected mice . . . . . . .. 39
c.,
van Keulen, L. J. M., Schreuder, B. E. Vromans, M. E. W.,
Langeveld, J. P. M., Smits, M. A.: Pathogenesis of natural scrapie in
sheep. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 57
Animal Models Jor Prion Diseases
Buschmann, A., Pfaff, E., Reifenberg, K., Muller, H. M., Groschup,
M. H.: Detection of cattle-derived BSE prions using transgenic mice
overexpressing bovine Prpc. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 75
Campbell, S., Dennehy, U., Telling, G.: Analyzing the influence of PrP
primary structure on prion pathogenesis in transgenic mice . . . . . .. 87
c.,
Manson, J. Barron, R., Jamieson, E., Baybutt, H., Tuzi, N.,
c.:
McConnell, I., Melton, D., Hope, J., Bostock, A single amino acid
alteration in murine PrP dramatically alters TSE incubation time. . . . .. 95
Harris, D. A., Chiesa, R., Drisaldi, B., Quaglio, E., Migheli, A.,
Piccardo, P., Ghetti, B.: A transgenic model of a familial prion
disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 103
Scott, M. R., Supattapone, S., Nguyen, H.-O. B., DeArmond, S. J.,
Prusiner, S. B.: Transgenic models of prion disease. . . . . . . . . .. .. 113
Epidemiology and Diagnosis oj Prion Diseases
Heim, D., Wilesmith, J. W.: Surveillance of BSE .............. 127
Contents
Vlll
Budka, H.: Histopathology and immunohistochemistry of human
transmissible spongiform encephalopathies (TSEs). . . . . . . . . . .. . 1.3 5
Ironside, J. W.: Pathology of variant Creutzfeldt-lakob disease. . .. 143
Poser, S., Zerr, I., Schroeter, A., Otto, M., Giese, A., Steinhoff, B. J.,
Kretzschmar, H. A.: Clinical and differential diagnosis of
Creutzfeldt-lakob disease. . . . . . . . . . . . . . . . . . . . . .. .. 15. 3. . . . .
Giese, A., Bieschke, J., Eigen, M., Kretzschmar, H. A.: Putting prions
into focus: application of single molecule detection to the diagnosis of
pnon dIseases. . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . 1. 6.1 . . . . . .
Schulz-Schaeffer, W. J., Fatzer, R., Vandevelde, M., Kretzschmar,
H. A.: Detection of Prpsc in subclinical BSE with the paraffin-em
bedded tissue (PET) blot. . . . . . . . . . . . . . . . . . . . . . . . . . .. ... . 173
Hunter, N., Goldmann, W., Marshall, E., O'Neill, G.: Sheep and goats:
natural and experimental TSEs and factors influencing incidence of
disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . .1 8. 1. . .
Oesch, B., Doherr, M., Heim, D., Fischer, K., Egli, S., Bolliger, S.,
Biffiger, K., Schaller, 0., Vandevelde, M., Moser, M.: Application of
Prionics Western blotting procedure to screen for BSE in cattle re
gularly slaughtered at Swiss abattoirs. . . . . . . . . . . . . . . . ... 1. 8.9 . .
Grassi, J., Creminon, c., Frobert, Y., Fretier, P., Turbica, I.,
Rezaei, H., Hunsmann, G., Comoy, E., Deslys, J.-P.: Specific
determination of the proteinase K-resistant form of the prion protein
using two-site immunometric assays. Application to the post-mortem
diagnosis of BSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 197
Characterization of the Infectious Agent
Chen, S. G., Zou, W., Parchi, P., Gambetti, P.: Prpsc typing by N
terminal sequencing and mass spectrometry . . . . . . . . . . . . . .2 .0 9 . . .
Groschup, M. H., Kuczius, T., Junghans, F., Sweeney, T., Bodemer, W.,
Buschmann, A.: Characterization of BSE and scrapie strains/isolates. 2 I 7
Safar, J., Cohen, F. E., Prusiner, S. B.: Quantitative traits of prion
strains are enciphered in the conformation of the prion protein . . . . 227
Structure and Function of PrP
Kretzschmar, H. A., Tings, T., Madlung, A., Giese, A., Herms, J.:
Function of Prpc as a copper-binding protein at the synapse ..... 239
Billeter, M., Wuthrich, K.: The prion protein globular domain and
disease-related mutants studied by molecular dynamics simulations . 251
Post, K., Brown, D. R., Groschup, M. H., Kretzschmar, H. A., Riesner,
D.: Neurotoxicity but not infectivity of prion proteins can be induced
reversibly in vitro. . . . . . . . . . . . . . . . . . . . . . . . . . . 2. 6.5 . . . . . . . .
Contents IX
Pr P Conversion
Demaimay, R., Chesebro, B., Caughey, 8.: Inhibition of formation of
protease-resistant prion protein by Trypan Blue, Sirius Red and other
Congo Red analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Vorberg, I., Pfaff, E., Groschup, M. H.: The use of monoclonal anti-
body epitopes for tagging PrP in conversion experiments ......... 285
Listed in Current Contents
Pathogenesis of Prion Diseases
Prions: from neurografts to neuroinvasion
M. Glatzel, M. A. Klein, S. Brandner, and A. Aguzzi
Institute of Neuropathology, University Hospital Zurich, Zurich
Summary. Spongiform encephalopathies are infectious neurodegenera
tive diseases caused by pathogens that seem to be devoid of any informa
tional nucleic acids. Histopathologically, these diseases are characterized by
spongiform degeneration of the central nervous system. Although the main
pathological changes during the course of the disease occur in the brain, the
infectious agent accumulates early in lymphoid tissue. The consecutive
development of clinical disease depends on the presence of an intact im
mune system including mature B-cells and follicular dendritic cells. In this
article we review the state of knowledge on the routes of neuroinvasion
used by the infectious agent in order to gain access to the central nervous
system upon entry into extracerebral sites.
Introduction
Prion diseases typically result in spongiform degeneration of the central
nervous system (eNS), yet the entry point of the infectious agent (termed
prion) is often through peripheral sites like the gastrointestinal tract. In this
article we review the transport mechanisms of prions within the eNS and
from the periphery to the eNS. Special emphasis is put on the role of the
lymphoreticular system (LRS) and the peripheral nervous system (PNS).
Neurografts in prion research
Prnp% mice show normal development and behavior [12, 36]. This fact has
led to the hypothesis that scrapie pathology may come about because Prpsc
deposition is neurotoxic [17], rather than by depletion of cellular Prpc [14].
To study the question of neurotoxicity of Prpsc, we exposed brain tissue of
Prnp% mice to a continuous source of Prpsc. This was done by grafting
neural tissue overexpressing Prpc into the brain of Prpc-deficient mice
using well-established protocols [25-27]. These mice were then intracere
brally inoculated with scrapie prions. As a result neuroectodermal grafts
accumulated high levels of Prpsc and infectivity and developed severe
histopathological changes characteristic for scrapie (Fig. 1). In mice that
