Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 250
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
OCR for page 251
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
OCR for page 252
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.
OCR for page 253
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.
OCR for page 254
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.
OCR for page 255
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.
OCR for page 256
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
OCR for page 257
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
OCR for page 258
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.
Representative terms from entire chapter:
infectious agent
