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aptamer: A small piece of DNA or RNA or a small peptide selected from a large pool of random DNA, RNA, or peptides based on the piece's ability to bind to a specific target. Targets may be proteins, many other kinds of small molecules, or even whole microorganisms. An aptamer tagged with an immunological or biochemical marker and bound to a protein can be used to detect that specific protein. If an aptamer binds specifically to PrPSc, it may have diagnostic or preventive potential. If the bound aptamer inter- feres with conversion of prpC to PrPSc, it may have therapeutic potential. bovine spongiform encephalopathy (BSE): A TSE that primarily affects cattle and that develops when cattle eat feed contaminated with the infec- tious agent of either scrapie or BSE. First identified in 1986 in the United Kingdom, BSE became an epidemic affecting hundreds of thousands of cattle in both the United Kingdom and Europe. It appears that some humans who ate beef or beef products containing the BSE agent have contracted variant Creutzfel~t-~akob disease, identified in 1996. Zoo animals fed beef or feed containing the BSE agent also have developed TSE. BSE: See bovine spongiform encephalopathy. huffy coat: The layer of white blood cells that lies at the top of the solid portion of centrifuged whole blood. cervid: A member of the Cervidae family of mammals. Males have solid, deciduous antlers. The only animals known to naturally contract chronic 250

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GLOSSARY 251 wasting disease are three cervid species: elk (Cervus e~phus), mule deer (Odocoileus hemonius), end white-tailed deer (Odocoileusvirginianus). chaotrope: A substance that can disrupt the structure of water to make non- polar substances water-soluble and that can denature proteins as a result. Chaotropes are used to study protein folding and the interactions of pro- teins with other molecules. chronic wasting disease (CWD): A TSE contracted by three North Ameri- can cervid species: white-tailed deer, mule deer, and elk. Identified in the early 1980s; origin unknown. Transmitted among the three species by an unknown mechanism suspected to involve material shed from infected ani- mals (e.g., urine, feces, saliva, hair, etch. There is no documented evidence that the disease is transmissible to humans, but it has been transmitted experimentally to cattle by intracerebral inoculation. Its name derives from the emaciated appearance of animals in the late stage of this disease. CID: See Creutzfel~t-~akob disease classical Creutzfel~t-lakob disease: Sometimes used when referring to spo- radic Creutzfel~t-~akob disease. codon: A sequence of three nucleotides on messenger RNA (mRNA) that code for an amino acid or a stop or start signal. The codon number relates to its position in the gene's nucleotide sequence or the position of the amino acid on the encoded protein. Creutzfel~t-lakob disease (CID): A fatal neurodegenerative prion disease in humans that is distinct from kuru. Some cases have an infectious or genetic origin, but most are of undetermined cause. There are several related dis- eases: cCID: See classical Creutzfel~t-~akob disease. fCJD: See familial Creutzfel~lt-~akob disease. iCJD: See iatrogenic Creutzfel~lt-lakob disease. nvCJD: See new variant Creutzfeldt-Jakob disease. sCID: See sporadic Creutzfeldt-~akob disease. vCJD: See variant Creutzfeldt-~akob disease. C-terminus: The carboxy! end of a protein. In PrP, the C-terminus is at- tached to a cell membrane by a glycosy! phosphatidylinosito! (GPI) moiety known as the GPI anchor. This anchor is added to the molecule when amino acids 231 through 253, known as the GPI signal sequence, are removed

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252 ADVANCING PRION SCIENCE during the process called transamidation. Two cystine amino acid residues form a tight bond in the C-terminus region. In addition various complex carbohydrates attach to asparagine amino acids in this region. epitope: A site on a large molecule to which a homologous antibody will bind. familial Creutzfel~t-lakob disease (fCID): A variety of CID in which cases cluster within families and are associated with mutations at one of several loci along the PRNP gene sequence. The phenotypic expression of fCTD depends on the mutation. Some forms of fCTD have been transmitted ex- perimentally to animals by intracerebral inoculation, demonstrating that these forms are prion diseases. fatal familial insomnia (FFI): A human transmissible spongiform encephal- opathy (TSE) due to a mutation in which the amino acid aspartic acid is substituted by the amino acid asparagine at codon 178 on the PRNP gene, and this mutation acts in concert with the expression of the amino acid methionine at polymorphic codon 129. This condition results in both neu- rological signs and autonomic dysfunction, including insomnia. FFI: See fatal familial insomnia. genotype: With respect to PrP, relates to the composition of the PRNP gene. Gerstmann-Straussler-Scheinker disease (GSS): A human TSE due to ge- netic mutation involving one of several loci along the PRNP gene in concert with the polymorphic expression of methionine or valine at codon 129. Although the clinical characteristics vary depending on the haplotype, this condition has a lengthier clinical course than most human TSEs, generally lasting several years. GSS: see Gerstmann-Straussler-Scheinker disease. haplotype: In general, refers to two sites, usually in proximity, along the same chromosome strand that are linked in terms of the phenotype they produce. In prion science, the term refers to the phenotypic effects of a mutation along the PRNP gene linked with a designated amino acid ex- pressed by a polymorphic co(lon. For example, the haplotype D178N-129M signifies that at codon 178, one amino acid, aspartic acid (D), is substituted by another, asparagine (N), in combination with methionine (M) expressed at codon 129. A different haplotype would be D178N-129V.

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GLOSSARY 253 iatrogenic Creutzfel~t-lakob disease (iCID): A form of CID that is trans- mitted through medical mishaps. Known cases of iC}D were caused by the transplantation of prior-contaminated human aura mater, injection of prior-contaminated human growth hormone from pituitary extracts, and reuse of surgical instruments and devices contaminated by prior use in a patient with C}D. ID50: The dose of an infectious agent sufficient to infect 50 percent of ex- posed animals or people. The size of an ID50 of a single infectious agent may vary depending on several factors, including the route of transmission. For example, the ID50 of prions necessary to cause infection by the oral route would be higher than the ID50 delivered directly into the brain by intracerebral inoculation. Since TSEs are fatal, the ID50 equals the LDso (L means lethal). The ID50 would not be equivalent to the LDrr~ if an asYmo- . . . Somatic carrier state existed . JU ~ 1 infectious unit (IU): The smallest amount of infectious agent leading to an infection in a single person or animal exposed. The single infectious unit is not necessarily equivalent to a single aggregate of PrPSC molecules. One IU likely consists of many aggregates of misfolded PrPSc. It is not known at present how the combination of number and size of aggregates influences infectivity. For example 400 aggregates each containing 1000 PrPSc mol- ecules (400,000 molecules) may confer more infectivity than 1000 aggre- gates each containing 500 PrPSc molecules (500,000 molecules). In addition to considering the physical composition of aggregated prion molecules, the amount of prions required to infect an animal or person will vary depend- ing on the route of transmission, the species of origin of the prion, and the genetic susceptibility of the host animal or person. In the absence of the ability to precisely count and measure the size of priors, specified lab ani- mals are used to control the variability mentioned. For example, if several groups of 20 mice each were experimentally exposed to prions by the in- tracerebral route (the most sensitive route), using a standard volume of material that was diluted 10-fold in each group of 20 mice, the highest dilution titer that causes a single case among the 20 mice contains one IU. The dilution titer that causes 10 of 20 of mice to become infected contains an IDso which is equivalent to the LDso. Consequently, an IU is at least 10- fold less than an ID50, by convention. Several IUs may be required to infect that same mouse strain by the intraperitoneal route and even more by the oral route. isoform: A protein molecule having the same primary structure (same amino acid sequence) as its counterpart, but a different three-dimensional shape.

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254 ADVANCING PRION SCIENCE isotype: A classification scheme for human CID based on the mobility of fragments of the PrPSc molecule following cleavage with proteinase K using gel electrophoresis and Western blot techniques. IU: See infectious unit. kuru: A TSE contracted by members of the Fore Tribe of Papua New Guinea, as well as a Fore word meaning "to tremble," one of the clinical signs of neurological degeneration among affected individuals. The infec- tious agent incubates for 4 to 40 years. Ethnological and epidemiological studies indicate that the infectious agent was transmitted during endocannibalistic funeral rituals in which women and children ate the brains of deceased relatives and spread the brain tissue on their bodies. Since this ritual was banned in 1957, the number of kuru cases has declined to a handful. LD50: A dose of an infectious agent that is lethal to 50 percent of the ex- posed population. See IDso. new variant Creutzfel~t-lakob disease (nvCID): The original name of the human disease caused by the infectious agent of bovine spongiform en- cephalopathy (BSE). It was described as a "new variant" of a known malady, Creutzfel~t-Takob disease. The disease is now called simply variant Creutzfel~t-~akob disease, or ACID. N-terminus: The unattached amino-terminal end of a protein molecule. In PrP, the N-terminus contains the signal peptide and five repeating octapep- tides, which have preferential binding affinity to copper. Offal: The parts of a butchered animal not processed into human food, generally including blood, internal organs, legs, head, and spinal cord. phenotype: With respect to PrP, relates to the metabolic, physiologic, and physical characteristics, both normal and pathological, exhibited by a host as a result of its PRNP gene expression interacting with the environment inside and outside the organism. polymorphism: Possession of two or more alleles of a gene that code for different amino acids at the same site along a protein sequence. The fre- quency of the alleles is greater than can be explained by naturally recurrent mutations. Polymorphisms appear to improve a host's resistance to infec- tious agents and to noxious environmental effects.

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GLOSSARY 255 prion: An acronym for "proteinaceous infectious particle." All known prions are misfolded isomers of a normal cellular protein coded by the Prnp gene. Aggregates of the misfolded protein of sufficient quantity and size are associated with TSE infectivity and neurodegenerative diseases in both ani- mals and humans. In mammals, prions are, at the present time, found pri- marily in nerve cells and lymphoreticular cells. Whether formed endog- enously or introduced from an external source, prions accumulate in cells by influencing the normal, cellular prion protein to assume the disease- associated isoform, which has limited resistance to digestion by proteinase K. Most but not all TSE experts favor the so-called protein-only theory, which contends that prions transmit TSE infections without accompanying nucleic acid. The preponderance of evidence suggests that prions may be the infectious agent of TSEs. However, a minority of respected TSE experts believe that the protein-only theory has not been proven beyond question. prion disease: A fatal, transmissible neurodegenerative disease associated with aggregates of PrPSC, an abnormally folded isoform of the cellular pro- tein PrP encoded by the Prnp gene. Often used synonymously with the term transmissible spongiform encephalopathy (TSE). See prion. prion protein: The normal isoform of a protein found mainly in the body's nerve cells. Its metabolic pathway and physiological function are currently unknown. This protein is sensitive to digestion by proteinase K. prion strain: A TSE isolate or source of infection that consistently matches agreed criteria or characteristics. These characteristics have included incu- bation period and the patterns of distribution and relative severity of the spongiform changes in the brain (the lesion profile). For scrapie, strain characterization has been defined mostly in terms of the reproducibility and stability of the disease phenotype on serial transmission in a specified in- bred mouse genotype. Newer criteria may include molecular conformation of the prion. PROP: The gene that codes for prion protein in humans. All letters are capitalized and in italics. Prnp: The gene that codes for prion protein in mice and other animals. Only the first letter is capitalized but all letters are in italics. proteinase K: A protease enzyme that is used to cleave proteins in vitro. It is obtained from the fungus Tritirachium album, which derives its carbon and nitrogen from keratin, from which the letter K derives. Often represented by the abbreviation PK.

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256 ADVANCING PRION SCIENCE PrP: Prion protein. In the absence of a superscript, it generally refers to the normal cellular prion protein, but in some cases it may refer to either the normal prion protein or its abnormal isoform. For example, antibodies to PrP may bind to both prpC and PrPSc. PrP/: Indicates the inability of the host animal to produce prion protein. Usually this refers to experimental knockout mice that have been geneti- cally manipulated to delete the Prop gene from both alleles on the autoso- mal chromosome that codes for prion protein. PrP 27-30: The fragment of the prion molecule that is most resistant to digestion by proteinase K. The numbers correspond to the molecular mass (in kilodaltons) of this prion fragment. See Western blot. PrPC: Normal cellular prion protein digestible by proteinase K. PrPCwD: Abnormally folded prion protein associated with a TSE called chronic wasting disease (CWD), which is known to occur in elk, mule deer, and white-tailed deer. The disease's name derives from the observation that infected animals at the clinical stage lose muscle mass and appear wasted. PrPreS: Abnormally folded prion protein that is highly resistant to proteinase K digestion and is strongly associated with prion disease. It is sometimes used synonymously with PrPSc. PrPSc: Abnormally folded prion protein that has a gradient of resistance to proteinase K digestion. It is associated with infectious potential and with prion disease even in circumstances where it may be sensitive to proteinase K digestion. pRpsen Prion protein that is sensitive to proteinase K digestion. Sometimes used synonymously with PrPC. rational drug design: The development of a drug based on foreknowledge of the three-dimensional structure and behavior of a specific molecule in- volved in a disease process. With this knowledge, drug developers can tar- get a specific binding site on the molecule to disrupt, enhance, or redirect its normal activity, thus interrupting the disease process. By contrast, tradi- tional drug development typically begins with a range of potentially thera- peutic chemical compounds that are narrowed down to the best candidates through empirical observation of their effects. Applying rational drug de- sign to transmissible spongiform encephalopathies (TSEs) would begin with the knowledge of differences between the tertiary structures of cellar prion

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GLOSSARY 257 protein (PrPC) and its misfolded isoform (PrPSC) as well as the identification of one or more epitopes on these proteins. Blocking or activating the epitopeks) could potentially disrupt an essential step in TSE pathogenesis, such as the conversion of prpC to PrPSc. scrapie: A TSE of sheep and goats. The TSE was first described by Scottish veterinarians in the 1700s, centuries before prions were first recognized. The modes of transmission are thought to be contact with infected sheep or goats or their placentas, contact with a scrapie-contaminated environment, or oral intake of scrapie agent-contaminated material. The "Sc" in the term PrPSC refers to scrapie. PrPSC is used to refer to the abnormal isoform of prEc associated with TSEs. species barrier: The genetic, metabolic, physiological, and physical differ- ences among species that result in variable susceptibility to an infectious agent. sporadic Creutzfel~t-lakob disease (sCID): The most common variety of CID. The cause is unknown. sC]D appears to occur worldwide at a rate of approximately one case per 1 million population. Most cases involve older adults. transgene: A gene from one organism that has been transferred and inte- grated into the DNA of another organism of the same or different species such that the transferred gene is expressed in the host organism. Investiga- tors conducting prion transmission studies use transgenes to convey un- natural molecular characteristics to experimental animals so as to circum- vent the species barrier. For example, it is easier to transmit BSE to a transgenic mouse with a bovine transgene than to a normal mouse. These experiments are further enhanced when the mouse's own PrP gene expres- sion is knocked out (PrP/~. transmissible spongiform encephalopathy (TSE): A general term that refers to all diseases associated with the presence of prions in vacuolated central nervous system tissue. Prions from TSE-affected brain tissue are believed to transmit the neurodegenerative disease state from the affected animal to another host. A synonym for prion disease. TSE: See transmissible spongiform encephalopathy. variant Creutzfel~t-lakob disease (vC3D): A clinical type of CID first iden- tified in 1996 and believed to result from the ingestion of beef products

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258 ADVANCING PRION SCIENCE containing the infectious agent of bovine spongiform encephalopathy (BSE). The majority of vCTD cases occur in young adults. Western blot: A technique used in molecular biology to detect and identify proteins in a test sample; also known as an immunoblot. A mixture of proteins is embedded in a slab of polyacrylamide gel and subjected to elec- trophoresis, during which an applied voltage causes the proteins to travel linearly toward the opposite end of the acrylamide slab at rates dependent on each protein's mass (measured in kilodaltons EkDa]) and charge. The pattern on the gel is transferred (blotted) to nitrocellulose paper or a nylon membrane. This paper is then probed with detector antibodies. This pro- tein-antibody complex is then bound with a labeled antiglobulin that visu- alizes a pattern of dark bands that vary in intensity depending upon the amount of protein in the sample. The test is usually run simultaneously on the same gel and paper with appropriate control specimens.