-------------- Enclosure number 1 ---------------- ------------------------------------------------------- SCIENCE-WEEK FREE TRIAL SUBSCRIPTION: This Focus Report is extracted from the full-text Email publication SCIENCE-WEEK. If you have not had a previous free trial subscription to SCIENCE-WEEK, you can subscribe for a 3-issue SW trial without any obligation on your part afterward. To obtain a trial subscription to SCIENCE-WEEK, simply transmit FREE TRIAL to <[EMAIL PROTECTED]>. Full SCIENCE-WEEK subscription details are appended to this file. ------------------------------------------------------- FOCUS REPORT: MEDICAL BIOLOGY: PRIONS A Summary Group from SCIENCE-WEEK ------------------------------------------------- ON THE PRION HYPOTHESIS Prions are a class of poorly understood proteins implicated in a number of exotic human neurological diseases and in some common animal diseases such as sheep scrapie and bovine spongiform encephalopathy in cattle ("mad cow disease"). One human disease in which prions have been strongly implicated is Creutzfeldt- Jakob disease, which appears to have a genetic basis in about 15% of the cases. The prion protein (denoted as PrP) is encoded by the host's chromosomal DNA, and an abnormal *isoform of the protein is the only known component associated with disease transmissibility. This abnormal isoform differs physically from the normal "cellular" protein form by its high *beta-sheet content, its insolubility in detergents, its propensity to aggregate, and its relative resistance to proteolysis. ... ... In a short review of the present status of research on prions, D. Westaway et al make the following points: 1) The benign cellular prion form, called Prp(supC) is a molecule that is most probably present in all mammals and expressed on the surfaces of neurons via a glycophosphatidylinositol anchor. The pathogenic form of the prion protein is called Prp(supSc) (Sc = scrapie) or Prp(sup res) (res = resistant to protease), and the cellular form apparently serves as a necessary precursor to the pathogenic form. 2) It is presently unclear whether subtypes of pathogenic prion protein are the true infectious agent, or whether such preparation harbor cryptic agents such as viruses or proviruses (nonviral or previral nucleic acid entities). 3) The simplest form of the "protein only" prion hypothesis proposes that infectious molecules can be produced by coercing the normal protein to adopt pathogenic conformations. 4) At least 11 possible prion ligands have been identified by in vitro binding and other techniques, but the situation concerning ligands is unclear: a) in no case have independent methods identified the same ligand in an unequivocal fashion; b) in no case have binding sites been mapped on prion proteins; c) in no case have ligand- prion binding affinities been estimated; and, d) in no case have any genetic methods been used to demonstrate binding in vivo. 5) In summary, although the prion hypothesis is not universally accepted, even skeptics concede that the prion protein is somehow involved in the control of disease susceptibility. At the other theoretical extreme, prion proteins are believed to comprise the prototype of a new class of infectious pathogens, with protein misfolding as a novel mechanism of pathogenesis, and with the suggestion that simple organisms may use prion-like mechanisms to switch physiological states and thereby adapt to new environments. ----------- D. Westaway et al (3 authors at 3 installations, CA UK US) Prions. (Proc. Natl. Acad. Sci. US 15 Sep 98 95:11030) QY: David Westaway, University of Toronto 416-979-4901 ----------- Text Notes: ... ... *isoform: Any one of the multiple forms of a functional protein that differ in amino acid sequence and electrophoretic mobility. ... ... *beta-sheet: (beta-conformation) One type of protein secondary structure. ------------------- Summary & Notes by SCIENCE-WEEK <http://scienceweek.com> 23Oct98 ------------------- Related Background: A TRANSMEMBRANE FORM OF THE PRION PROTEIN A transgenic mouse is a mouse into which genetic material from another organism has been transferred, the transferred and incorporated new mouse genes then being expressed with the resultant production of specific proteins. Prions are a class of poorly understood proteins implicated in a number of exotic human neurological diseases and in some common animal diseases such as sheep scrapie and bovine spongiform encephalopathy in cattle ("mad cow disease"). The "endoplasmic reticulum" is an extensive system of flattened membranous sacs in the cytoplasm of cells, important in protein and lipid biosynthesis, translocation of synthesized molecules, and continuous with the nuclear envelope. ... ... Hegde et al (9 authors at Univ. of California San Francisco, US) report a study with transgenic mice expressing prion protein mutations that alter the relative ratios of the topological forms of the molecule. Expression of a particular endoplasmic reticulum transmembrane form (Ctm) of the protein produced neurodegenerative changes in mice similar to those of some genetic prion diseases, and brains from these mice contained this form of the protein but not the isoform responsible for transmission of prion diseases. The authors suggest that aberrant regulation of protein biogenesis and topology at the endoplasmic reticulum can result in neurodegeneration, and that proteins undergoing topological regulation such as Ctm-prion protein may be involved in neurogenerative diseases besides those currently attributed to prions. QY: Vishwanath R. Lingappa <[EMAIL PROTECTED]>; Stanley B. Prusiner, Univ. of Calif. San Francisco 415-476-4044. (Science 6 Feb 98) (Science-Week 20 Feb 98) ------------------- Related Background: ON PROTEIN FOLDING IN PRION AND AMYLOID DISEASES What is remarkable about prions is that although they behave as infectious agents, they are 100 times smaller than viruses and their mechanism of replication is unknown. All the prion diseases are apparently associated with the accumulation in the brain of an abnormal protease-resistant isoform of the prion protein PrP. In other words, an abnormal variant of the normal PrP is somehow copied or produced by the disease process, which can be initiated by introducing infectious prion into the system. Denaturation is an irreversible change in solubility and other properties of proteins when they are exposed to various conditions, including heat and an acidic environment. The denatured protein essentially loses all its higher order structure and becomes a simple uncoiled/unfolded polymer. A lysosome is a cytoplasmic membrane-bound vesicle 5 to 8 nanometers in diameter and containing a variety of glycoprotein hydrolytic enzymes used to digest foreign material or defective organelles. The term "amyloid" refers to a group of chemically diverse proteins composed of linear nonbranching aggregated fibrils that occur as pathological extracellular deposits in various diseases (including several neurodegenerative diseases). ... ... J. Kelly (Scripps Research Institute, US), in a comment- ary on prion proteins, suggests that the conversion of normal to pathogenic prion protein likely occurs in the partially denatur- ing environment of a cellular compartment such as a lysosome, where the lower pH environment (or another factor-environment) "effects the conformational changes that facilitate amyloid and prion self-assembly". The author suggests that using the structure of normal prion protein to design high-affinity ligands to what appear to be critical higher-order molecular structure regions may lead to an understanding of the structural changes required for pathogenic amyloid fibril formation. QY: Jeffrey W. Kelly, Scripps Research Institute 619-784-1000 (Proc. Natl. Acad. Sci. US 3 Feb 98) (Science-Week 20 Feb 98) ------------------- Related Background: A CRITICISM OF THE PRION HYPOTHESIS Spongiform encephalopathies are a type of brain disease found in humans and animals and are characterized by macroscopic vacancies produced by the disease process (the brain has a sponge-like appearance). "Transmissible spongiform encephalopathies" such as bovine spongiform encephalopathy ("mad cow disease") and human Creutzfeldt-Jakob disease are diseases that apparently involve an infectious agent. Prions are a class of poorly understood proteins implicated in transmissible spongiform encephalopathies, but there is controversy about this, since the details of the prion infectious process are unknown (cf. background material below). ... ... Now C. Farquhar (Institute for Animal Health Edinburgh, UK), in a letter to the journal Nature, notes that the prion hypothesis is far from proven, and that alternative hypo- theses of the nature of the causative agent of the transmissible spongiform encephalopathies are being misrepresented and dismiss- ed. The "virino" hypothesis, for example, which is not a convent- ional virus hypothesis, proposes an agent-specific replicable informational molecule, yet to be identified, bound to a protect- ive host prion protein. The author emphasizes that the precise nature of a prion still eludes identification, and that the prion hypothesis has yet to explain satisfactorily the many strains of transmissible spongiform encephalopathies. In conclusion, the author suggests that the discovery of an informational molecule with strain-specific properties, for example a nucleic acid, would refute a prion protein-only hypothesis, and that until the matter is settled, it should be recognized there may be more to the biological diversity of transmissible spongiform encephalopathies than prion protein. QY: Christine F. Farquhar <[EMAIL PROTECTED]> (Nature 22 Jan 98) ------------------- Related Background: MORE EVIDENCE THAT PRION PROTEIN BINDS COPPER IN VIVO ... A chelate is a metal coordination complex in which one ligand coordinates at two or more points to the same metal ion, and a glycine chelate is a chelate involving the amino acid glycine. Brown et al (13 authors at 4 installations, DE CA UK) report that the amino-terminal domain of normal prion protein exhibits 5 to 6 sites that bind copper presented as a glycine chelate, that genetically engineered mice deprived of prion protein show severe copper reductions in various cell membrane fractions and altered electrophysiological responses to excess copper. The authors suggest their findings indicate that normal prion protein can exist in a copper-metalloprotein form in vivo, and that like other cuproproteins implicated in the pathogenesis of neurolog- ical disease, prion proteins may regulate copper distribution. QY: Hans Kretschmer <[EMAIL PROTECTED]> (Nature 18/25 Dec 97) ------------------- Related Background: AN APPARENT INVOLVEMENT OF PRION PROTEIN IN COPPER BINDING Copper is essential as a trace metal for the function of certain enzymes and other biomolecules, but even a moderate excess can be highly toxic in certain tissues. ... At a recent meeting of the Society for Neuroscience (24-30 Oct New Orleans, US) David Brown (Univ. of Cambridge, UK) reported that normal prion protein apparently binds copper ions and thus protects neurons against the cytotoxic effects of the metal. He suggests the transformed disease-causing prion protein might not be able to perform this important function. But this idea is not without problems, since there is evidence that in genetically engineered mice without normal prion protein there is no resulting pathology -- which in turn suggests it is the transformed protein that is directly pathogenic. (Science 21 Nov 97) ------------------- Related Background: PRION DISEASES AND BOVINE SPONGIFORM ENCEPHALOPATHY ... Prions are apparently able to induce certain other proteins into pathogenic conformations, and these proteins in turn can cause the same effect in other proteins of the same class. None of this is yet well understood. One human disease in which prions have been strongly implicated is Creutzfeldt-Jakob disease (CJD), which appears to have a genetic basis in about 15% of the cases. Recently, there has been much concern in Europe concerning the possible infection of humans who might eat meat from prion-infected cows. The fears were at first dismissed by the medical community because of lack of evidence to support the idea, but recently some evidence has appeared, and the level of concern has increased significantly. Stanley B. Prusiner, who recently received the Nobel Prize in Physiology and Medicine for his work with prions, reviews the relation between prion diseases and the current bovine spongiform encephalopathy crisis. The author urges more attention to the fatal disorders of protein conformation that are apparently involved in prion diseases, and he suggests studies of prion proteins may have important applications to understanding Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. QY: S. B. Prusiner, Univ. of Calif. San Francisco, Neurology (415) 476-4044. (Science 10 Oct 97) ------------------- Related Background: ... Andrew F. Hill et al (8 authors at 3 installations, UK) report that the biological and molecular transmission charac- teristics of a variant of human Creutzfeldt-Jakob disease are consistent with it being the human counterpart of bovine spongi- form encephalopathy; and M. E. Bruce et al (13 authors at 4 installations, UK) report that interim results of transmissions of sporadic classical Creutzfeldt-Jakob disease and the new variant Creutzfeldt-Jakob disease to mice, such transmissions producing effects apparently identical to those produced by transmissions of bovine spongiform encephalopathy to mice, provide strong evidence that the same agent strain is involved in both bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. QY: John Collinge, Prion Disease Group, Imperial College, London UK; M. E. Bruce <[EMAIL PROTECTED]> (Nature 2 Oct 97) ------------------- Related Background: ... Rudi Glockshuber et al (Swiss Federal Institute of Tech- nology) report the first complete determination of the structure of a full-length prion protein: 208 amino acids, including a trio of helices and an unfolded tail 97 amino acids long. Evidence indicates it is the unfolded tail that may be involved in disease processes. Chemical techniques were used to reconstitute the folding of the full-length protein, and then nuclear magnetic resonance was used to determine the structure. This may be an important step to understanding how prions become pathogenic. (F.E.B.S. Letters 18 Aug 97) ------------------- Related Background: ... Thomas Blattner et al (University of Zurich, CH) report that mutant mice that do not produce normal PrP cannot be infected by the scrapie producing prion variant that ordinarily infects mice that do produce the normal protein. They conclude that transfer of infectivity to the central nervous system, the major event in the disease process, is crucially dependent on the expression of PrP in some as yet unknown tissue compartment. The fact that there is at least a useful laboratory animal model for the study of these poorly characterized infectious agents leaves one optimistic that an understanding of the essentials of prion pathogenesis may soon be forthcoming. QY: Adriano Aguzzi <[EMAIL PROTECTED]> (Nature 4 Sep 97) -------------------- Copyright (c) 1997,1998 Science-Week/Spectrum Press All Rights Reserved for information: http://scienceweek.com [EMAIL PROTECTED] -------------------- SCIENCE-WEEK Subscriptions: ----------------------------------------------- Please note: Educational and other nonprofit institutions and organizations are eligible for group subscription rates for SCIENCE-WEEK: 50+ subscribers at a subscription rate of US$1 per year per subscriber, with SW delivered individually to each Email address. For more complete information about group subscriptions, please query at: <[EMAIL PROTECTED]> ----------------------------------------------- SCIENCE-WEEK INDIVIDUAL SUBSCRIPTION INFORMATION: ------------------------------------------------- Subscriptions run for 52 issues at a cost of US$10.00 for the year, and begin with the next issue following receipt of payment. 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