Biological Sciences
Prions
Prions are infectious proteins that can cause neurodegenerative diseases in humans and animals. Unlike viruses or bacteria, prions do not contain genetic material but can induce abnormal folding of normal cellular proteins, leading to the formation of toxic aggregates in the brain. This can result in conditions such as Creutzfeldt-Jakob disease, mad cow disease, and scrapie.
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10 Key excerpts on "Prions"
eBook - PDFCreating Life from Life
Biotechnology and Science Fiction
- Rosalyn W. Berne(Author)
- 2014(Publication Date)
- Jenny Stanford Publishing(Publisher)
Prion diseases are caused by an enigmatic infectious agent that, unlike all other known pathogens, lacks genetic material (i.e., DNA, RNA). The infectious agent in these diseases is referred to as the prion and is composed primarily, if not solely, of misfolded forms of a normal cell surface protein. The normal form of the protein (denoted by PrP C , where “C” is for cellular) is produced in many tissues throughout the body but especially in the nervous system. Disease-associated forms of the PrP are denoted by PrP TSE (Brown and Cervenakova, 2005). Unlike bacterial pathogens, Prions are not alive; unlike viruses they do not induce cells to make new infectious proteins from scratch. Instead, PrP TSE promotes the misfolding of pre-existing PrP C to the disease-associated state. During the preclinical and clinical phases of prion diseases, Prions are present in the nervous system as well as the bloodstream and, in at least some species, are excreted in feces, urine, and saliva. Prions are notoriously resistant to sterilization methods that are effective against conventional pathogens (e.g., bacteria, viruses, fungi). They withstand autoclaving under conditions typically used to sterilize medical equipment (Taylor, 2000). Boiling, treatment with alcohol, formaldehyde, or protein-degrading enzymes and irradiation with ultraviolet light, microwaves, or ionizing radiation have little effect on the infectious agent (Taylor, 2000). Remarkably, even incineration at 600°C (1080°F) for 15 minutes has been reported to not completely eliminate prion infectivity (Brown et al., 2004). Prions survive wastewater treatment (Hinckley et al., 2008) and can persist in the environment for years (Brown and Gajdusek, 1991; Seidel et al., 2007). At present, diagnosis of prion diseases before clinical symptoms manifest is difficult because well-established detection methods lack the sensitivity necessary to detect Prions
- Karl Maramorosch(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
Because of these differences, the term prion was introduced to denote this novel class of infectious pathogens. The word, prion, was derived from proteinaceous and infectious because the first macromolecule to be identified within the scrapie agent was a protein (Prusiner, 1982). The definition of a prion must remain operational until its entire structure is known: Prions are small proteinaceous infectious parti-cles which are resistant to inactivation by most procedures that modify nucleic acids (Prusiner, 1982). At present, we still do not know if the prion contains a nucleic acid. It is unlikely that Prions contain genes coding for their pro-teins; however, the presence of a small nucleic acid or oli-gonucleotide within the interior of the prion has not been excluded. Certainly if Prions are comprised of protein alone or a nucleoprotein complex with a polynucleotide too small to code for the prion protein, these features will distinguish 340 S T A N L E Y B . P R U S I N E R ET AL. them from viruses (Prusiner, 1982). A protein of M r 27,000-30,000 is a structural macro-molecule within the prion and is denoted by the symbol, PrP, from prion protein (McKinley et al., 1983). This termino-logy is analogous to that used for structural ^iral proteins denoted VP. Genetic loci controlling the incubation periods in sheep and mice have been found. In sheep the alleles of this locus have been termed SIP from short incubation period and LIP from long incubation period (Dickinson, 1976). Two and per-haps three loci in mice have been discovered. The first was called SINC from Scrapie intubation (Dickinson and Meikle, 1969). The second locus to be described has been found for both scrappie and CJD in mice; it is called PID-1 from prion incubation determinant (Kingsbury et al ., 1983). At present, it is unclear whether or not a third locus exists which is sex-linked. An additional note concerns the term incubation time interval assay (Prusiner et al. y 1982b).
- Dongyou Liu(Author)
- 2016(Publication Date)
- CRC Press(Publisher)
Section V Prions This page intentionally left blank This page intentionally left blank 901 99 Bovine Spongiform Encephalopathy Akikazu Sakudo and Takashi Onodera 99.1 INTRODUCTION Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurological diseases that include Creutzfeldt– Jakob disease (CJD) in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, transmissible mink enceph-alopathy in minks, feline spongiform encephalopathy in cats, and exotic ungulate encephalopathy in zoo animals such as the kudu, nyala, gemsbok, eland, and oryx. The prion agent of each disease is named after the disease itself (e.g., CJD agent in CJD, scrapie agent in scrapie). A key event in the development of prion diseases is the conversion of the cellular, host-encoded prion protein (PrP C ) to its abnormal isoform (PrP Sc ) predomi-nantly in the central nervous system (CNS) of the infected host [1]. This chapter will introduce the molecular detection of BSE as well as the fundamental aspects of the disease. 99.1.1 C LASSIFICATION To understand the causative pathogens, information on their chemical composition will provide important clues. Reports published in 1980 indicated that the scrapie agent was inac-tivated by proteases [2,3] or by treatment with modified or denatured proteins [4,5]. These studies demonstrated that the scrapie agent required a protein but did little to discriminate it structurally from other infectious particles [6]. The knowl-edge that a protein was involved undoubtedly motivated sci-entists to improve both the method for purifying the scrapie agent and techniques for identifying agent-specific proteins. The discovery of PrP Sc and PrP C initiated a period of remark-able progress in this field by providing physical and diagnostic markers for prion diseases [7].
eBook - PDF- Dr. Yury O. Chernoff(Author)
- 2007(Publication Date)
- CRC Press(Publisher)
Another model, designated here and further as model of “adaptive prionization”, suggests that prion formation by itself could be an adaptive process, so that certain Prions are responsible for adaptive traits (e. g., see ref. 23). Prion Pathology” Model Mammalian Prion Diseases and Other Aggregation-Related Diseases Examples of the “prion diseases” are well known and include various infectious neurodegenerative diseases in mammals.15,16According to the “protein only” concept, which is now accepted by the majority of experts, the PrP protein in its prion form (PrPSc) is the sole component of a “transmissible particle” that is responsible for the genesis and transmission of a disease. Usually, there is a correlation between the disease and cerebral accumulation of PrP.3,24 The properties of PrP are very similar to those seen in various noninfectious amyloidoses and neural inclusion disorders, a large and heterogeneous group including more than 20 human diseases, among them Alzheimer s, Huntingtons and Parkinsons diseases,25 resulting from con version of certain proteins or their fragments from the normally soluble form to insoluble fibrils or plaques. Although protein-destabilizing mutations can confer the ability to form amyloids in vivo even to such commonly known proteins as lysozyme,26 usually disease-related aggrega tion depends on the presence of the specific elements of the primary structure.
eBook - PDF- Roger Kurlan(Author)
- 2006(Publication Date)
- CRC Press(Publisher)
3 Dementia in Prion Disorders Simon Hawke Brain and Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia INTRODUCTION Prion diseases or transmissible spongiform encephalopathies are the most feared and fulminant of the dementias. Often rapidly fatal and without effective therapy, the disorders are also transmissible by exposure to infectious tissues or body fluids, raising major public health concerns. The prion diseases comprise sporadic, inherited, and iatrogenic subtypes (for reviews see Refs. 1–4) and include Creutzfeldt-Jakob disease (CJD), the most common of the human prion diseases, and animal diseases, such as scrapie of sheep and goats, and bovine spongiform encephalopathy (BSE or mad cow disease) (reviewed in 5). Scrapie is endemic in many countries and has been recognized for over 200 years (reviewed in 6). Other prion disorders, such as BSE, variant CJD, and the so-called exotic ungulate encephalopathies have only recently emerged as disease entities. Other rarer human prion diseases include Kuru, which is confined to the Fore tribe in the highlands of New Guinea, Gerstmann-Straussler-Scheinker (GSS) disease, and fatal familial (FFI) and sporadic fatal insomnia (FI) (Table 1). Prion diseases have characteristic neuropathology, with spongiform degeneration of neurones and a marked astrocytic reaction in the brains of affected humans and animals, the extent of which varies between the disease sub-types. A hallmark of prion diseases is the deposition of an abnormally folded isoform (designated PrP Sc or PrP res ) of a cell-surface sialoglycoprotein, cellular prion protein or PrP C . PrP C is expressed to high levels in neurones and glia and also outside the central nervous system (CNS) on diverse cell types. It is 57 largely alpha helical and detergent soluble without a well characterized function, and refolds without post-translational modification into the pathogenic isoform, PrP Sc .
eBook - PDFPrions
A Challenge for Science, Medicine and the Public Health System
- H. F. Rabenau, J. Cinatl, H. W. Doerr, A. Schmidt, H. Herwald(Authors)
- 2004(Publication Date)
- S. Karger(Publisher)
These findings support the gen-eral concept of prion diseases. In summary, prion diseases are exceptional also in the sense that they can have an infectious as well as a sporadic or familial etiology. Thus, it is a great merit of the prion concept as well as convincing sup-port for it that diseases of quite different etiologies can be reduced to a unique phenomenon. TSEs – The Prion Theory 11 Outlook Since the transition of PrP C to infectious PrP Sc cannot yet be performed in the test tube, biophysical results on the structure and structural transitions of PrP will be rated as high, as they might lead to the desired in vitro PrP C → PrP Sc transition which then would represent the ultimate proof of the prion model. It will not matter whether a physical, chemical, enzymatic or any other treatment of PrP C is applied as long as infectivity is newly generated from a noninfectious PrP C sample. At present it is not clear whether the conformation of PrP Sc is already present in the monomeric PrP, in an oligomeric state or how big the smallest size of the infectious entity might be. Infectious Prions are only avail-able as large aggregates; is this an artifact from the preparation or an intrinsic feature of the infectious state? The potential hidden difficulty is evident from the finding that about 10 5 PrP molecules are needed for one infectious unit.
eBook - PDF- Brian K. Nunnally, Ira S. Krull, Brian K. Nunnally, Ira S. Krull(Authors)
- 2003(Publication Date)
- CRC Press(Publisher)
2 Prions, the Protein Hypothesis, and Scientific Revolutions David C. Bolton New York State Institute for Basic Research in Developmental Disabilities, Staten Island , New York, U.S.A. I. INTRODUCTION The protein hypothesis of the structure of transmissible spongiform enceph alopathy agents (or Prions1) radically altered the scientific view of infectious pathogens. Thomas Kuhn, in his classic analysis of science history and philosophy The Structure o f Scientific Revolutions (1), has described this type of change as a paradigm shift and the entire process as a scientific revolution. In this chapter, I examine the transition from a conventional microbiological paradigm (the virus hypothesis) to a new paradigm (the protein hypothesis) within K u h n ’s framework and show that the transition to the prion paradigm follows the pattern of previous scientific revolutions. Anomalous observa tions accumulated and precipitated a crisis in the field, from which radical new hypotheses appeared. A period of extraordinary science ensued wherein five major hypotheses for the structure of these unusual agents (the virus, membrane, virino, protein, and genetic hypotheses) competed to explain the key inconsistencies. Over time, the membrane and genetic hypotheses lost ground and the virus, virino, and prion hypotheses came to predominate. Now, after more than three decades, the revolution appears to be drawing to a close and it seems likely that the prion hypothesis will be the new paradigm that succeeds in displacing the previously accepted virus hypothesis. This transition, however, does not depend on formal proof of the prion hypothesis 21 -- 22 Bolton or on disproof of the virus or virino hypotheses; rather, the paradigm shift has occured because a majority of scientists believe that the prion hypothesis provides the best model for explaining key observations.
eBook - PDFNeurogenetics
Scientific and Clinical Advances
- David R. Lynch(Author)
- 2005(Publication Date)
- CRC Press(Publisher)
‘‘abnormal gait,’’ is characterized as a progressive gait ataxia in conjunction with behavioral abnormalities, myoclonus, and a progressive course to death. The pathologic features of kuru and CJD overlap with scrapie, a natural disease of sheep, also known to be transmissible. Each produced extensive vacuolation of the neuropil, also referred to as ‘‘spongiform change’’ (4). This eventually prompted experiments leading to the successful transmission of kuru to chimpanzees, followed shortly thereafter by the transmission of CJD (5,6). The source of kuru was eventually traced to the brain of affected individuals honored during cannibalistic rituals. Women and children, who had the greatest contact with the brain, developed kuru with the greatest frequency. Carleton Gadjusek was awarded a Nobel Prize for his work on kuru. A second Nobel Prize was awarded years later to Stanley Prusiner, for his discovery of the etiologic agent of these diseases; he designated this novel infectious agent, composed largely if not entirely of a protein, a prion (7). PRION PROTEIN (PrP) AND THE PRION CONCEPT PrP is a 253 amino acid (209 amino acid in its mature form) host-encoded cell surface glycoprotein highly expressed in nervous tissues, and especially within neuronal synapses (8). The protein is present in all vertebrates, and although there are some variations, the protein is generally well conserved. The normal function of PrP is unknown, although its roles in synaptic function (9–11), copper binding and delivery (12–14), and cell signaling (15) have all been sup-ported. In the original line of mice in which the PrP gene was ablated ( Prnp % ), no obvious phenotype or alteration of life span was observed, suggesting a noncritical or redundant function of PrP (16). The central feature of PrD is the accumulation of a pathogenic ‘‘scrapie-associated’’ isoform (PrP Sc ) of PrP, a conformational deviant of the normal cellular isoform (PrP C ).
eBook - PDF- Dana M. Santos(Author)
- 2011(Publication Date)
- Apple Academic Press(Publisher)
Chapter 5 Prion Disease Pathogenesis Ajay Singh, Maradumane L. Mohan, Alfred Orina Isaac, Xiu Luo, Jiri Petrak, Daniel Vyoral, and Neena Singh INTRODUCTION Converging evidence leaves little doubt that a change in the conformation of prion protein (PrP C ) from a mainly α -helical to a β -sheet rich PrP-scrapie (PrP Sc ) form is the main event responsible for prion disease associated neurotoxicity. However, neither the mechanism of toxicity by PrP Sc , nor the normal function of PrP C is entirely clear. Recent reports suggest that imbalance of iron homeostasis is a common feature of prion infected cells and mouse models, implicating redox-iron in prion disease patho-genesis. In this report, we provide evidence that PrP C mediates cellular iron uptake and transport, and mutant PrP forms alter cellular iron levels differentially. Using human neuroblastoma cells as models, we demonstrate that over-expression of PrP C increases intracellular iron relative to non-transfected controls as indicated by an increase in total cellular iron, the cellular labile iron pool (LIP), and iron content of ferritin. As a result, the levels of iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) are decreased, and expression of iron storage protein ferritin is increased. The positive effect of PrP C on ferritin iron content is enhanced by stimulating PrP C endo-cytosis, and reversed by cross-linking PrP C on the plasma membrane. Expression of mutant PrP forms lacking the octapeptide-repeats, the membrane anchor, or carrying the pathogenic mutation PrP 102L decreases ferritin iron content significantly relative to PrP C expressing cells, but the effect on cellular LIP and levels of Tf, TfR, and ferritin is complex, varying with the mutation.
eBook - PDF- Dongyou Liu(Author)
- 2016(Publication Date)
- CRC Press(Publisher)
9. Perrier, V., et al., Dominant-negative inhibition of prion rep-lication in transgenic mice, Proc. Natl. Acad. Sci. USA , 99, 13079, 2002. 10. Chiesa, R., et al., Molecular distinction between pathogenic and infectious properties of the prion protein, J. Virol ., 77, 7611, 2003. 11. Chesebro, B., et al., Anchorless prion protein results in infec-tious amyloid disease without clinical scrapie, Science , 308, 1435, 2005. 12. Gajdusek, D. C., et al., Kuru: Clinical pathological and epide-miological study of an acute progressive disease of the cen-tral nervous system among natives of the Eastern Highland of New Guinea, Amer. J. Med ., 26, 442, 1959. 13. Gajdusek, D. C., et al., Degenerative diseases of the central ner-vous systems in New Guinea: The endemic occurrence of “kuru” in the native population, N. Engl. J. Med ., 257, 974, 1959. 14. Hadlow, W. J., Scrapie and kuru, Lancet , 2, 289, 1959. 15. Prusiner, S. B., et al., Kuru with incubation periods exceeding two decades, Ann. Neurol ., 12, 1, 1982. 16. Zigas, V., et al., Kuru: Clinical study of a new syndrome resem-bling paralysis agitants in natives of the Eastern Highlands of Australian New Guinea, Med. J. Aust ., 2, 745, 1957. 17. Sigurdsson, B., Rida, a chronic encephalitis of sheep: With general remarks of infections which develop slowly and some of their characteristics, Br. Vet. J ., 110, 341, 1954. 18. Gadjusek, D. C., Unconventional viruses and the origin and disappearance of kuru, Science , 197, 943, 1977. 19. Come, J. H., et al., A kinetics model for amyloid formation in the prion diseases: Importance of seeding, Proc. Natl. Acad. Sci. USA , 99, 5959, 1993. 20. Hendrix, J. C., et al., A convergent synthesis of the amyloid protein of Alzheimer’s disease, J. Amer. Chem. Soc ., 114, 7930, 1992. 21. Jarett, J. T., et al., The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implication for the pathogenesis of Alzheimer’s disease, Biochemistry , 32, 4693, 1993.
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