Search

"Science is nothing but trained and organized common sense, differing from the latter only as a veteran may differ from a raw recruit."a Prion disease is a disease of the second half of the twentieth century, but the scientific method that has elucidated this fascinating group of diseases is much older. As an illustration of this, this chapter considers the way in which a nineteenth century scientist might have reacted to the challenge that prion disease has presented. T. H. Huxley (1825-1895) was an ardent naturalist, who traveled around the world collecting specimens, and who peered down the microscope (1). He amassed vast amounts of data, and could work prodigiously hard. His approach to science can be judged from some of things that he said. He was a confrontational character, and would undoubtedly have joined in the arguments that led to the concept of prion disease, if he had lived a century later. [ABSTRACT FROM AUTHOR]

The basis of strain vartation in scrapie and other transmissible spongrform encephalopathies is a crucial issue in the ongoing debate about the nature of the infectious agent. The clear evidence for the existence of multiple strains leads us to conclude that these agents carry some form of stram-specific information that determines the characteristics of the disease Any valid molecular model must, therefore, include an informational component that can be replicated in the infected host. Further, the behavior of strains when serially passaged in different host species or genotypes limits the range of possible models for the informational component of the agent In this chapter the methods used for agent strain discrimination are described. The strategies used for the isolation and passaging of dtfferent strains are presented and the implications of the results of these simple experiments are discussed. [ABSTRACT FROM AUTHOR]

It seems unlikely that anyone could have foretold the interest, controversy, and concern that the occurrence of bovine spongiform encephalopathy (BSE) in cattle in Great Britain would cause when the author was commissioned to investigate its epidemiology in the spring of 1987. The epidemic has proved to be the largest food-borne epidemic of a transmissible spongiform encephalopathy (TSE), and has been the subject of detailed scrutmy epidemiologically, by international agencies and governments, and by representatives of all types of media worldwide. During the course of the epidemic an attempt has been made to decipher the epidemiology of BSE with the usual objectives, the most important being to provide a model of causation such that necessary statutory controls could be identified and enacted to protect animal and human health, both in Great Britain and abroad. [ABSTRACT FROM AUTHOR]

In spite of the widespread use of immunocytochemical methods and the commensurate increase in the range of available techniques, a consistent means of electron miroscopical antigen localization in the lipid-rich central nervous system (CNS) has yet to be established. However, some successes have been achieved, most notably in neuroanatomy studies Combined morphological and histochemical techniques for the study of neuronal microcircuits have been described (1). Many of the antigens investigated in the CNS, such as neurotransmitters, appear not to withstand conventional electron microscopical fixation and embedding methods and consequently pre-embedding methods are employed (2). Pre-embedding immunocytochemistry unfortunately suffers from the disadvantages of unpredictable antibody penetration and suboptimal morphological structure. [ABSTRACT FROM AUTHOR]

The pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) appears to be based on the posttranslational conversion of the host's protease-sensitive prion protein (PrP-sen or PrPc) to abnormal protease-resistant forms (PrP-res or PrPSc). In vitro studies using both scrapie-infected tissue culture cells and cell-free reactions have been used effectively to help define the cellular and molecular details of this process and how it might be inhibited. Here we discuss experimental approaches that we have used in these studies [ABSTRACT FROM AUTHOR]

Prion encephalopathies are neurodegenerative diseases characterized by the accumulation of abnormal isoforms of the prion protein (PrP) and the deposition of PrP amyloid in the central nervous systein (CNS) (1, 2) The diseasespecific PrP molecules are distinguishable froin their normal homologs by their relative resistance to proteinase K digestion (1, 2), they are thought to be derived from protease-sensitive precursors by a posttranslational process that involves a conformational change with a shift from α-helix to β-sheet structure (3-5) [ABSTRACT FROM AUTHOR]

Henry Ford thought that hlstory was bunk; Hegel is supposed to have said that "people and governments never have learnt anything from history," and Disraeli advised us to "read no history." The authors of this chapter are less dismissive, taking the alternative view that those who ignore history are destined to repeat It, which is the view that underscores this essay on the response to Bovine Spongiform Encephalopathy (BSE); an unforeseen disease, induced by human activity, that had important impacts on government and veterinary and medical affairs. It is unlikely that such an event will occur again, at least in exactly the same way, but it is worth telling the story of how scientific findings contributed in planned and unplanned ways and how the complex nexus of regulations, the legislature, the media, and international relations developed; we learned lessons along the way that we believe could be applied with profit in the face of another such epidemic. The account is not intended to be comprehensive: It is a selective and incomplete history that concentrates on the most important issues. A chronology (see Table 1) that relates events to control measures gives further details, and a brief reading list is provided for those who wish to study the subject in greater detail. [ABSTRACT FROM AUTHOR]

Like conventrinal viruses, prion isolates exhibit distinctive, and often restricted host-ranges. However, the molecular events that shape the hostranges of these two classes of pathogen are dissimilar, reflecting their fundamentally different life cycles. As discussed by Ridley and Baker (Chapter 1), many lines of experimentation indicate that PrPSc, an aberrant form of a hostencoded neuronal sialoglycoprotein PrPc, is the major constituent of the scrapie prion. Resistance to protease digestion in vitro is a convenient hallmark of prpSc, prpc or a closely related protease-sensitive macromolecule is converted to PrPSc in a posttranslational event: This event may correspond to a conformational change templated by PrPSc molecules (1, 2). Whereas the host-range and cellular tropism of mammalian viruses frequently reflects their binding to cell-surface proteins to gain entry into cells via endocytosis, PrPSc-receptors have yet to be identified: Although PrPc plays a critical role in determining prion host-range (see the following) and is displayed on the cell surface via a glycolipid anchor (3), three observations suggest that it cannot be considered a "receptor" in the conventional sense, e.g., in the sense that CD4 is the receptor for HIV. First, the cell surface molecules co-opted by mammalian viruses cycle within the endocytic pathway and are destined for degradation: During prion repllication PrPc is converted to PrPSc and changes a variety of biophysical properties (4). [ABSTRACT FROM AUTHOR]

The Transmissible Spongiform Encephalopathies (TSEs), such as scrapre, BSE, and Creutzfeldt-Jakob disease, are associated with alterations in the neural membrane protein or prion protein (PrP). This chapter will outline the gene targeting approaches that have been used to mutate the murine PrP gene, resulting in mice with reduction or absence of the PrP protein. It will then describe how these transgenuic animals can contribute to our understanding of the role of PrP in agent replication, the pathology of the TSEs, and the normal function of PrP [ABSTRACT FROM AUTHOR]

Scrapie, as a disease of sheep and goats, has been recognized for over 300 yr and was first documented in England in 1730 (1). Sheep breeders petitioned the House of Commons of King George II in 1754 requesting the enforcing of regulations governing the sale and distribution of sheep This is believed to have been prompted by a major scrapie epizootic However, the petition was referred to "the consideration of a Committee" and vanished without a trace (2)—not so different from the present day! [ABSTRACT FROM AUTHOR]

Neurological disorders impose a severe burden on affected individuals Inherited neurological disorders of late onset present their own specific difficulties in terms of genetic counseling, management, and patients' psychological adaptation. Huntington's disease (HD) is the archetypal late-onset neurogenetic disorder. It is an autosomal-dominant disorder usually of adult onset in which progressive degeneration of the cerebral cortex and basal ganglia result in choreiform movements and progressive mental deterioration. Closely linked genetic markers have been available since 1983 so that presymptomatic testing protocols have been in development longer for this disorder than for any other similar disorder (for further information on HD specifically see ref. 1). In this chapter we highlight the major issues we consider relevant to achieving optimal diagnostic, predictive, and prenatal testing and to the family management of individuals from HD families. We put forward the protocols we have developed to help clinicians and other allied workers approach these difficult areas. [ABSTRACT FROM AUTHOR]

This chapter reviews all proven or highly probable cases of environmentally acquired human spongiform encephalopathy (cannibalism, neurosurgical procedures, cornea1 and dura mater homografts, and natrve pituitary hormone therapy), and evaluates potential but as yet unverified environmental sources of disease, such as peripheral tissue homografts, organ transplants, administranon of blood, blood products, and other biologicals, occupational exposures, and zoonotic infections. Implicit in this breviary of known and putative origins of envtronmentally acquired disease are laboratory and epidemiologic methods for recognizing and if possible preventing subsequent cases both from present and future sources of infection. [ABSTRACT FROM AUTHOR]

In contrast to animal prion diseases, the human forms of prion disease are rare and include Creutzfeldt-Jakob disease (CJD), kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). Meticulous epidemiological research has demonstrated that kuru was caused by cross-contamination in the course of ritual cannibalism (1), whereas advances in molecular biology have provided powerful evidence that familial forms of human Piion disease, including GSS and FFI, are linked to mutations within the priori protein (PrP) gene (2-4). The cause of sporadic CJD remains unknown despite both extensive epidemiological research and the remarkable advances in the understanding of pathogenic mechanisms in priori diseases. [ABSTRACT FROM AUTHOR]

Some fatal degenerative encephalopathies of mammals form a distinct group because they are caused by unconventional but uncharacterized transmissible agents that evoke no classical iminune response in the affected host. The animal diseases are bovine spongiform encephalopathy (BSE), chronic wasting disease of elk and mule-deer, feline spongiform encephalopathy (FSE) of the domestic cat, scrapie in sheep and goats, and transmissible mink encephalopathy (TME). A number of exotic ruminant and felid species maintained in, or originating from, zoological collections in the United Kingdom have also developed fatal encephalopathies that, like FSE, are considered to have been caused by BSE agent; the affected species are cheetah, eland, gemsbok, kudu, nyala, ocelot, oryx, and puma. The human diseases are Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler-Scheinker syndrome (GSS), and kuru. [ABSTRACT FROM AUTHOR]

Traditionally, confirmation of Transmissible Sponglform Encephalopathy (TSE) disease in humans or animals is by conventional light microscopy of stained tissue sections prepared from specific sites of formalin-fixed tissue after embedding in paraffin wax. This is the statutory method of confirmation of Bovine Spongiform Encephalphathy (BSE) in the United Kingdom and it is also used in other Member States of the European Community. However, two additional diagnostic criteria for TSE, the detection of disease-specific fibrils by transmission electron microscopy and the detection of the main constituent of the fibrils, an abnormal protein by immunoblotting, have also been reported. The former is the current method of confirmation for the statutory diagnosis of scrapie in the United Kingdom. [ABSTRACT FROM AUTHOR]

Routine histological examination of cases of Creutzfeldt-Jakob disease (CJD) reveals a spectrum of pathological involvement, particularly with regard to the extent and localization of spongiform change. Although there is no difficulty in confirming a diagnosis of CJD in cases with widespread and severe spongiform change involving the cortical gray matter or cerebellar molecular layer, all too often the cortex may be only minimally or focally affected, and in some cases pathological changes are largely confined to the basal ganglia or cerebellum. Unless wide-ranging pathological examination is undertaken, the diagnosis of CJD may be missed in such cases. Thus is a particular problem in the interpretation of cortical biopsies in cases of suspected CJD and is one reason why biopsy in such cases is now discouraged (1). In addition, there are other conditions that give rise to spongy appearances in the gray matter (2) and the difficulties of achieving a firm diagnosis of CJD, based on conventional histological appearances, have been outlined in Chapter 3. Occasional reports of the coexistence of CJD with other dementing illnesses, particularly Alzhelmer disease, also add to the dragnostic difficulties (3). CJD is a rare disease (0.5 cases/million of the population/yr) and it is likely that individual experience of the possible range of CJD pathological changes will be limited. For all of these reasons, it would be useful to develop some additional method of confirming the diagnosis of CJD in tissue sections. Since it is now known that CJD and related diseases are associated with accumulation in the brain of a protease-resistant protein known as prion protein (4), the demonstration of prion presence in suspected cases would represent such a devolopment. [ABSTRACT FROM AUTHOR]