Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein
Proc Natl Acad Sci USA 1994 Oct 11;91(21):9936-40
Telling GC; Scott M; Hsiao KK; Foster D; Yang SL;
Torchia M; Sidle KC; Collinge J; De Armond SJ; Prusiner SB
Department of Neurology, University of California,
San Francisco 94143. MJ - Brain [pathology]; Chimeric Proteins [biosynthesis];
Creutzfeldt-Jakob Syndrome [genetics] [physiopathology]; Prions [biosynthesis]
MN - Astrocytes [metabolism] [pathology]; Brain [metabolism]; Chimeric
Proteins [analysis]; Creutzfeldt-Jakob Syndrome [pathology]; Mice, Transgenic;
Mice; Open Reading Frames; Polymerase Chain Reaction [methods]; Prions
[analysis] [genetics]; Restriction Mapping; Time Factors MT - Animal; Human;
Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE
Transgenic (Tg) mice were constructed that express
a chimeric prion protein (PrP) in which a segment of mouse (Mo) PrP was
replaced with the corresponding human (Hu) PrP sequence.
The chimeric PrP,
designated MHu2MPrP, differs from MoPrP by 9 amino acids between residues
96 and 167.
All of the Tg(MHu2M) mice developed neurologic disease approximately
200 days after inoculation with brain homogenates from three patients dying
of Creutzfeldt-Jakob disease (CJD).
Inoculation of Tg(MHu2M) mice with
CJD prions produced MHu2MPrPSc (where PrPSc is the scrapie isoform of PrP);
inoculation with Mo prions produced Mo-PrPSc. The patterns of MHu2MPrPSc
and MoPrPSc accumulation in the brains of Tg(MHu2M) mice were different.
About 10% of Tg(HuPrP) mice expressing HuPrP and non-Tg mice developed
neurologic disease 500 days after inoculation with CJD prions.
The different
susceptibilities of Tg(HuPrP) and Tg(MHu2M) mice to Hu prions indicate
that additional species-specific factors are involved in prion replication.
Diagnosis, prevention, and treatment of Hu prion diseases should be facilitated
by Tg(MHu2M) mice.
EM - 9501
IS - 0027-8424 LA - English
UI - 95024076 RN - 0 (Chimeric Proteins); 0 (Prions)
Perceptions of prion disease
J Clin Pathol 1994 Oct;47(10):876-9
Ridley RM MJ - Prion Diseases [diagnosis] MN - Adolescence;
Adult; Aged; Brain [pathology]; Child, Preschool; Child; Infant; Middle
Age; Mutation; Nerve Tissue Proteins [genetics]; Pedigree; Prion Diseases
[genetics]; Prions [genetics] MT - Female; Human; Male PT - JOURNAL ARTICLE;
REVIEW (15 references); REVIEW, TUTORIAL EM - 9502
IS - 0021-9746 LA - English
UI - 95051609 RN - 0 (Nerve Tissue Proteins); 0 (Prions)
Absence of disease related prion protein in neurodegenerative
disorders presenting with Parkinson's syndrome
J Neurol NeuroSurg Psychiatry 1994 Oct;57(10):1249-51
Jendroska K; Hoffmann O; Schelosky L; Lees AJ; Poewe
W; Daniel SE
Department of Neurology, Universitatsklinikum Rudolf
Virchow, Berlin, Germany. MJ - Brain [pathology]; Parkinson Disease [pathology];
Prions [analysis] MN - Brain Diseases [pathology]; Creutzfeldt-Jakob Syndrome
[pathology]; Dementia, Presenile [pathology]; Immunohistochemistry; Nerve
Degeneration; Supranuclear Palsy, Progressive [pathology] MT - Human; Support,
Non-U.S. Gov't PT - JOURNAL ARTICLE
Movement disorders presenting with parkinsonism may
share histopathological features with Creutzfeldt-Jakob disease, a spongiform
encephalopathy caused by the accumulation of pathological prion protein
in brain.
To investigate a possible aetiological link between these conditions
and Creutzfeldt-Jakob disease, histoblot Immunostaining for pathological
prion protein was carried out in 90 cases including idiopathic Parkinson's
disease, multiple system atrophy, diffuse Lewy body disease, Steele-Richardson-Olszewski syndrome, corticobasal degeneration, and Pick's disease.
Pathological prion
protein was identified in four controls with Creutzfeldt-Jakob disease
but not in any of the other diseases examined. The findings suggest that
an aetiological role for prions in these movement disorders is unlikely.
Histoblotting provides a useful method for screening large areas of tissue
for the presence of pathological prion protein and may be helpful in the
differential diagnosis of difficult cases.
EM - 9501
IS - 0022-3050 LA - English
UI - 95016781 RN - 0 (Prions)
Neuropathological phenotype and 'prion protein' genotype correlation
in sporadic Creutzfeldt-Jakob disease
NeuroSci Lett 1994 Sep 26;179(1-2):50-2
de Silva R; Ironside JW; McCardle L; Esmonde T; Bell
J; Will R; Windl O; Dempster M; Estibeiro P; Lathe R
National Creutzfeldt-Jakob disease surveillance unit,
Western General Hospital, Edinburgh, UK. MJ - Creutzfeldt-Jakob Syndrome
[genetics] [pathology]; Prions [biosynthesis] MN - Aged, 80 and over; Aged;
Amyloidosis [pathology]; Amyloid [genetics] [metabolism]; Creutzfeldt-Jakob
Syndrome [metabolism]; DNA [analysis]; Genotype; Methionine [metabolism];
Middle Age; Open Reading Frames; Phenotype; Polymerase Chain Reaction;
Polymorphism (Genetics); Prions [genetics]; Valine [metabolism] MT - Human
PT - JOURNAL ARTICLE
A systematic study of 'prion protein' genotype in cases
of sporadic Creutzfeldt-Jakob disease showing amyloid plaques staining
with anti-prion protein antibody has been performed.
This revealed a relative
excess of cases with valine at position 129 of the gene's open reading
frame.
The observation emphasises the importance of this site of common
polymorphism in influencing the NeuroPathological phenotype in human spongiform
encephalopathy.
EM - 9505
IS - 0304-3940 LA - English
UI - 95148156 RN - 0 (Amyloid); 0 (Prions); 7004-03-7
(Valine); 7005-18-7 (Methionine); 9007-49-2 (DNA)
Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein
Proc Natl Acad Sci USA 1994 Sep 13;91(19):9126-30
Hsiao KK; Groth D; Scott M; Yang SL; Serban H; Rapp
D; Foster D; Torchia M; Dearmond SJ; Prusiner SB
Department of Neurology, University of California,
San Francisco 94143. MJ - Gerstmann-Straussler Syndrome [genetics]; Prions
[genetics]; Scrapie [genetics] MN - Hamsters; Mesocricetus; Mice, Transgenic;
Mice; Mutation; Prions [metabolism]; Scrapie [pathology] [transmission]
MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT -
JOURNAL ARTICLE
Two lines of transgenic (Tg) mice expressing high (H)
levels of the mutant P101L prion protein (PrP) developed a neurologic illness
and central nervous system pathology indistinguishable from experimental
murine scrapie; these mice were designated Tg(MoPrP-P101L)H.
Brain homogenates
from Tg(MoPrP-P101L)H mice were inoculated intracerebrally into CD-1 Swiss
mice, Syrian hamsters, and Tg196 mice, Tg mice expressing the MoPrP-P101L
transgene at low levels.
None of the CD-1 mice developed central nervous
system dysfunction, whereas approximately 10% of hamsters and approximately
40% of the Tg196 mice manifested neurologic signs between 117 and 639 days
after inoculation.
Serial transmission of neurodegeneration in Tg196 mice
and Syrian hamsters was initiated with brain extracts, producing incubation
times of approximately 400 and approximately 75 days, respectively.
Although
the Tg(MoPrP-P101L)H mice appear to accumulate only low levels of infections
prions in their brains, the serial transmission of disease to inoculated
recipients argues that prion formation occurs de novo in the brains of
these uninoculated animals.
These Tg mouse studies, taken together with
similar findings in humans dying of inherited prion diseases, provide additional
evidence that prions lack a foreign nucleic acid.
EM - 9412
IS - 0027-8424 LA - English
UI - 94377505 RN - 0 (Prions); 0 (PrPSc Proteins)
Mechanism of scrapie replication
[letter; comment] CM - Comment
on: Science 1994 Apr 22; 264(5158):530-1
Science 1994 Sep 9;265(5178):1510
Lansbury PT MJ - Prions [chemistry] MN - Polymers;
Prions [biosynthesis]; Protein Folding PT - COMMENT; LETTER EM - 9412
IS - 0036-8075 LA - English
UI - 94360231 RN - 0 (Polymers); 0 (Prions)
Neurodegeneration in humans caused by prions
West J Med 1994 Sep;161(3):264-72
Prusiner SB
Department of Neurology, University of California,
San Francisco, School of Medicine 94143-0518. MJ - Nerve Degeneration [physiology];
Prion Diseases [physiopathology] MN - Prion Diseases [diagnosis] [genetics]
[metabolism] [transmission]; Prions [genetics] [metabolism] MT - Animal;
Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL
ARTICLE; REVIEW (114 references); REVIEW, TUTORIAL
Prion diseases include kuru, Creutzfeldt-Jakob disease,
Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia of
humans as well as scrapie and bovine spongiform encephalopathy of animals.
For many years, the prion diseases were thought to be caused by viruses
despite evidence to the contrary.
The unique characteristic common to all
of these disorders, whether sporadic, dominantly inherited, or acquired
by infection, is that they involve aberrant metabolism of the prion protein.
In many cases, the cellular prion protein is converted into the scrapie
variant by a process after translation that involves a conformational change.
Often the human prion diseases are transmissible experimentally to animals,
and all of the inherited prion diseases segregate with prion protein gene
mutations.
EM - 9502
IS - 0093-0415 LA - English
UI - 95066029 RN - 0 (Prions) ID - NS14069-NS-NINDS;
AG08967-AG-NIA; AG02132-AG-NIA; +
Cell-free formation of protease-resistant prion protein
[see
comments] CM - Comment in: Nature 1994 Aug 11; 370(6489):419-20
Nature 1994 Aug 11;370(6489):471-4
Kocisko DA; Come JH; Priola SA; Chesebro B; Raymond
GJ; Lansbury PT; Caughey B
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge 02139. MJ - Peptide Peptidohydrolases [metabolism];
Prions [metabolism] MN - Alzheimer's Disease [metabolism]; Cell-Free System;
Hamsters; Mice; Protein Denaturation; Tumor Cells, Cultured MT - Animal;
Human; Support, U.S. Gov't, Non-P.H.S. PT - JOURNAL ARTICLE
The infectious agent (or 'prion') of the transmissible
spongiform encephalopathies (TSEs) such as scrapie resembles a virus in
that it replicates in vivo and has distinct strains, but it was postulated
long ago to contain only protein.
More recently, PrPSc, a Pathogenic, scrapie-associated form of the host-encoded prion protein (PrP), was identified as a possible primary TSE agent protein. PrPSc is defined biochemically by its insolubility and resistance to proteases and is derived post-translationally from normal, protease-sensitive PrP (PrPc).
The conversion seems to involve conformational
change rather than covalent modification. However, the conversion mechanism
and the relationship of PrPSc formation to TSE agent replication remain
unclear.
Here we report the conversion of PrPc to protease-resistant forms
similar to PrPSc in a cell-free system composed of substantially purified
constituents.
This conversion was selective and required the presence of
preexisting PrPSc, providing direct evidence that PrPSc derives from specific
PrPc-PrPSc interactions.
EM - 9411
IS - 0028-0836 LA - English
UI - 94322940 RN - EC 3.4.- (Peptide Peptidohydrolases);
0 (Prions); 0 (PrPSc Proteins)
NeuroBiology. Catching the culprit prion
[news; comment] CM
- Comment on: Nature 1994 Aug 11; 370(6489):471-4
Nature 1994 Aug 11;370(6489):419-20
Beyreuther K; Masters CL MJ - Peptide Peptidohydrolases
[metabolism]; Prions [metabolism] MN - Cell-Free System; Prion Diseases
[transmission]; Prions [chemistry]; Protein Conformation MT - Animal; Human
PT - COMMENT; NEWS EM - 9411
IS - 0028-0836 LA - English
UI - 94322932 RN - EC 3.4.- (Peptide Peptidohydrolases);
0 (Prions)
Genetics. Psi no more for yeast prions
[news]
Nature 1994 Aug 4;370(6488):327-8
Tuite MF MJ - Prions [genetics]; Saccharomyces cerevisiae
[genetics] MN - Amino Acid Sequence; Molecular Sequence Data; Phenotype
MT - Human PT - NEWS EM - 9411
IS - 0028-0836 LA - English
UI - 94322902 RN - 0 (Prions)
Prion protein is necessary for normal synaptic function
Nature 1994 Jul 28;370(6487):295-7
Collinge J; Whittington MA; Sidle KC; Smith CJ; Palmer
MS; Clarke AR; Jefferys JG
Department of Biochemistry and Molecular Genetics,
St Mary's Hospital Medical School, Imperial College, London, UK. MJ - Prions;
Synapses [physiology] MN - Action Potentials; GABA [metabolism]; Hippocampus
[physiology]; Mice, Inbred C57BL; Mice; Nerve Degeneration; Prion Diseases
[physiopathology]; Pyramidal Cells [physiology] MT - Animal; In Vitro;
Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE
The prion diseases are neurodegenerative conditions,
transmissible by inoculation, and in some cases inherited as an autosomal
dominant disorder.
They include Creutzfeldt-Jakob disease in humans and
scrapie and bovine spongiform encephalopathy in animals.
The prion consists
principally of a post-translationally modified form of a host-encoded glycoprotein
(PrPC), designated PrPSc (ref. 1); the normal cellular function of PrPC
is, however, unknown.
Although PrP is highly conserved among mammals and
widely expressed in early embryogenesis, mice homozygous for disrupted
PrP genes appear developmentally and behaviorally normal.
PrP is a protein
anchored to the neuronal surface by glycosylphosphatidylinositol, suggesting
a role in cell signalling or adhesion.
Here we report that hippocampal
slices from PrP null mice have weakened GABAA (gamma-aminobutyric acid
type A) receptor-mediated fast inhibition and impaired long-term potentiation.
This impaired synaptic inhibition may be involved in the epileptiform activity
seen in Creutzfeldt-Jakob disease and we argue that loss of function of
PrPC may contribute to the early synaptic loss and neuronal degeneration
seen in these diseases.
EM - 9410
IS - 0028-0836 LA - English
UI - 94309735 RN - 0 (Prions); 56-12-2 (GABA)
Proposed three-dimensional structure for the cellular prion protein
Proc Natl Acad Sci USA 1994 Jul 19;91(15):7139-43
Huang Z; Gabriel JM; Baldwin MA; Fletterick RJ; Prusiner
SB; Cohen FE
Department of Pharmaceutical Chemistry, University
of California, San Francisco 94143. MJ - Prions [chemistry] MN - Amino
Acid Sequence; Circular Dichroism; Crystallography, X-Ray; Molecular Sequence
Data; Nuclear Magnetic Resonance; Protein Structure, Secondary; Protein
Structure, Tertiary; Spectrophotometry, Infrared MT - Animal; Human; Support,
Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE
Prion diseases are a group of neurodegenerative disorders
in humans and animals that seem to result from a conformational change
in the prion protein (PrP).
Utilizing data obtained by circular dichroism
and infrared spectroscopy, computational studies predicted the three-dimensional
structure of the cellular form of PrP (PrPc).
A heuristic approach consisting
of the prediction of secondary structures and of an evaluation of the packing
of secondary elements was used to search for plausible tertiary structures.
After a series of experimental and theoretical constraints were applied,
four structural models of four-helix bundles emerged.
A group of amino
acids within the four predicted helices were identified as important for
tertiary interactions between helices. These amino acids could be essential
for maintaining a stable tertiary structure of PrPc.
Among four plausible
structural models for PrPc, the X-bundle model seemed to correlate best
with 5 of 11 known point mutations that segregate with the inherited prion
diseases.
These 5 mutations cluster around a central hydrophobic core in
the X-bundle structure. Furthermore, these mutations occur at or near those
amino acids which are predicted to be important for helix-helix interactions.
The three-dimensional structure of PrPc proposed here may not only provide
a basis for rationalizing mutations of the PrP gene in the inherited prion
diseases but also guide design of genetically engineered PrP molecules
for further experimental studies.
EM - 9410
IS - 0027-8424 LA - English
UI - 94316653 RN - 0 (Prions); 0 (PrPSc Proteins)
Prions and public health
[editorial]
Nature 1994 Jul 7;370(6484):2 MJ - Creutzfeldt-Jakob
Syndrome [transmission]; Encephalopathy, Bovine Spongiform [transmission];
Meat; Prions; Public Health MN - Cattle; Germany; Great Britain MT - Animal;
Human PT - EDITORIAL EM - 9409
IS - 0028-0836 LA - English
UI - 94286000 RN - 0 (Prions)
Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice
Proc Natl Acad Sci USA 1994 Jun 7;91(12):5690-4
Carlson GA; Ebeling C; Yang SL; Telling G; Torchia
M; Groth D; Westaway D; De Armond SJ; Prusiner SB
McLaughlin Research Institute, Great Falls, MT 59405.
MJ - Prions [genetics] [Pathogenicity]; Scrapie [genetics] MN - Alleles;
Brain [metabolism]; Mice, Inbred Strains; Mice, Transgenic; Mice; Prions
[metabolism] MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't,
P.H.S. PT - JOURNAL ARTICLE
Different prion isolates, often referred to as "strains,"
present an enigma because considerable evidence argues that prions are
devoid of nucleic acid.
To investigate prion diversity, we inoculated three
"strains" of prions into congenic and transgenic mice harboring variable
numbers of two different alleles, designated a and b, of the prion protein
(PrP) structural gene, Prn-p.
The length of the incubation time was inversely
related to the number of Prn-p(a) genes in mice inoculated with the Rocky
Mountain Laboratory (RML) prion strain.
Results with mice lacking this
locus (Prn-p0/0) and transgenic mice argue that long incubation times are
not a dominant trait as thought for many years.
But rather they are due
to reduced levels of the substrate PrPC-A (cellular isoform of PrP, allotype
A) in (Prn-p(a) x Prn-pb)F1 mice.
In contrast, the Prn-p(a) gene extended
incubation times in mice inoculated with the 87V and 22A prion strains,
whereas the Prn-pb gene was permissive.
Experiments with the 87V isolate
suggest that a genetic locus distinct from Prn-p controls deposition of
the scrapie isoform of PrP (PrPSc) and attendant NeuroPathology.
Each prion
isolate produced distinguishable patterns of PrPSc accumulation in brain;
of note, the patterns in Prn-p(a) and Prn-pb congenic mice inoculated with
RML prions were more different than those in congenic Prn-pb mice with
RML or 22A prions.
Our results suggest that scrapie "strain-specific" incubation
times can be explained by differences in the relative efficiency of allotypic
interactions that lead to conversion of PrPC into PrPSc.
EM - 9409
IS - 0027-8424 LA - English
UI - 94261652 RN - 0 (Prions); 0 (PrPSc Proteins)
Murine scrapie-infected neurons in vivo release excess prion protein into the extracellular space
NeuroSci Lett 1994 Jun 6;174(1):39-42
Jeffrey M; Goodsir CM; Bruce ME; McBride PA; Fowler
N; Scott JR
Lasswade Veterinary Laboratory, Midlothian, Scotland,
UK. MJ - Neurons [metabolism]; PrPC Proteins [metabolism]; Prions [metabolism];
Scrapie [metabolism] MN - Brain [microbiology] [pathology]; Extracellular
Space [drug effects] [metabolism]; Immunohistochemistry; Mice; Neurons
[microbiology] [ultrastructure]; Scrapie [microbiology] [pathology] MT
- Animal PT - JOURNAL ARTICLE
An originally heretical proposition that the transmissible
spongiform encephalopathies are caused by a host-coded protein (the prion
hypothesis) is now current dogma.
Indeed these disorders are commonly called
prion diseases but the prion hypothesis provides no readily acceptable
explanation for the source of the informational component of the agent
necessary to code for the diversity of strains of scrapie.
Ultrastructural
Immunolocalisation of prion protein (PrP) in murine scrapie shows that
PrP accumulates in association with the plasmalemma of neurones, diffusing
from the neuronal cell surface into the extracellular space around small
neurites.
Prior to aggregation and fibril assembly. These events occur without
the involvement of other cell types.
The area of neuropil infiltrated with
extracellular PrP around infected neurons and neurites indicates that the
form of PrP initially produced is not immediately amyloidogenic.
EM - 9502
IS - 0304-3940 LA - English
UI - 95060196 RN - 0 (Prions); 0 (PrPC Proteins)
Familial Pick's disease and dementia in frontal lobe degeneration of non-Alzheimer type are not variants of prion disease
[letter]
J Neurol NeuroSurg Psychiatry 1994 Jun;57(6):762
Collinge J; Palmer MS; Sidle KC; Mahal SP; Campbell
T; Brown J; Hardy J; Brun AE; Gustafson L; Bakker E; et al MJ - Dementia,
Presenile [genetics]; Frontal Lobe; Mutation [genetics]; Prion Diseases
[genetics] MN - Brain Diseases [genetics]; Middle Age; Pedigree MT - Case
Report; Female; Human PT - LETTER EM - 9409
IS - 0022-3050 LA - English
UI - 94275488
Inherited prion diseases
Proc Natl Acad Sci USA 1994 May 24;91(11):4611-4
Prusiner SB
Department of Neurology, University of California,
San Francisco 94143-0518. MJ - Prion Diseases [genetics]; Prions [genetics]
MT - Animal; Human PT - JOURNAL ARTICLE; REVIEW (68 references); REVIEW,
TUTORIAL EM - 9409
IS - 0027-8424 LA - English
UI - 94255375 RN - 0 (Prions)
Rapid anterograde Axonal transport of the cellular prion glycoprotein
in the peripheral and central nervous systems
J Biol Chem 1994 May 20;269(20):14711-4
Borchelt DR; Koliatsos VE; Guarnieri M; Pardo CA;
Sisodia SS; Price DL
Department of Pathology, Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205-2196. MJ - Brain [physiology];
Ganglia, Spinal [physiology]; Nerve Tissue Proteins [metabolism]; Neurons
[physiology]; Prions [metabolism]; Sciatic Nerve [physiology] MN - Axonal
Transport; Brain [metabolism]; Cell Line; Electrophoresis, Polyacrylamide
Gel; Ganglia, Spinal [metabolism]; Hamsters; Mesocricetus; Methionine [metabolism];
Nerve Endings [metabolism] [physiology]; Neurons [metabolism]; Organ Specificity;
Prions [biosynthesis] [isolation & purification]; Rabbits [Immunology];
Rats, Sprague-Dawley; Rats; Sciatic Nerve [metabolism]; Sulfur Radioisotopes
MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT -
JOURNAL ARTICLE
In prion diseases, the cellular prion protein (PrPc),
abundant in neurons, is converted posttranslationally into an amyloid-forming
scrapie prion protein (PrPSc), which accumulates in white matter tracts
and nerve terminals.
The trafficking of PrPc in neurons was investigated
in vivo by injecting [35S]methionine into the L4 and L5 dorsal root ganglia
and the entorhinal cortices of adult rats and by tracing the movement of
radiolabeled PrPc.
In both paradigms, labeled 33-35-kDa PrPc was transported,
within 4 h, to distal axons and nerve terminals cofractionating with proteins
in the fast component.
Future studies using these methods may allow us
to determine whether PrPc is converted into PrpSc during Axonal transport
and whether PrPSc is transported in animals with prion diseases.
EM - 9408
IS - 0021-9258 LA - English
UI - 94237891 RN - 0 (Nerve Tissue Proteins); 0 (Prions);
0 (PrPSc Proteins); 0 (Sulfur Radioisotopes); 7005-18-7 (Methionine) ID
- AG 05146-AG-NIA; NS 20471-NS-NINDS; NS 10580-NS-NINDS
[URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae
[see comments] CM - Comment in: Science 1994
Apr 22; 264(5158):528-9
Science 1994 Apr 22;264(5158):566-9
Wickner RB
Section on Genetics of Simple Eukaryotes, National
Institute of Diabetes and Digestive and Kidney Diseases, National Institutes
of Health, Bethesda, MD 20892. MJ - Fungal Proteins [genetics]; Saccharomyces
cerevisiae [genetics] MN - Aspartic Acid [analogs & derivatives] [metabolism];
Base Sequence; Crosses, Genetic; Fungal Proteins [chemistry] [metabolism];
Genes, Dominant; Genes, Fungal; Genes, Recessive; Guanidines [pharmacology];
Molecular Sequence Data; Mutation; Phenotype; Plasmids; Prions [chemistry]
[genetics] [metabolism]; Saccharomyces cerevisiae [metabolism] PT - JOURNAL
ARTICLE
A cytoplasmically inherited element, [URE3], allows
yeast to use ureidosuccinate in the presence of ammonium ion. Chromosomal
mutations in the URE2 gene produce the same phenotype.
[URE3] depends for
its propagation on the URE2 product (Ure2p), a negative regulator of enzymes
of nitrogen metabolism.
Saccharomyces cerevisiae strains cured of [URE3]
with guanidium chloride were shown to return to the [URE3]-carrying state
without its introduction from other cells.
Overproduction of Ure2p increased
the frequency with which a strain became [URE3] by 100-fold. In analogy
to mammalian prions, [URE3] may be an altered form of Ure2p that is inactive
for its normal function but can convert normal Ure2p to the altered form.
The genetic evidence presented here suggests that protein-based inheritance,
involving a protein unrelated to the mammalian prion protein, can occur
in a microorganism.
EM - 9407
IS - 0036-8075 LA - English
UI - 94212170 RN - 0 (Fungal Proteins); 0 (Guanidines);
0 (Plasmids); 0 (Prions); 0 (PrPSc Proteins); 113-00-8 (guanidine); 134773-68-5
(URE2 protein); 56-84-8 (Aspartic Acid); 923-37-5 (ureidosuccinic acid)
Structural clues to prion replication
[see comments] CM - Comment
in: Science 1994 Sep 9; 265(5178):1510
Science 1994 Apr 22;264(5158):530-1
Cohen FE; Pan KM; Huang Z; Baldwin M; Fletterick RJ;
Prusiner SB
Department of Medicine, University of California,
San Francisco 94143-0518. MJ - Prion Diseases [metabolism]; Prions [biosynthesis]
MN - Mice, Transgenic; Mice; Models, Biological; Mutation; Prion Diseases
[transmission]; Prions [chemistry] [genetics] [metabolism]; Protein Conformation;
Protein Structure, Secondary MT - Animal; Support, Non-U.S. Gov't; Support,
U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE EM - 9407
IS - 0036-8075 LA - English
UI - 94212166 RN - 0 (Prions); 0 (PrPSc Proteins)
Human prion diseases
Ann Neurol 1994 Apr;35(4):385-95
Prusiner SB; Hsiao KK
Department of Neurology, University of California,
San Francisco 94143-0518. MJ - Prion Diseases [genetics] MN - Adult; Aged;
Linkage (Genetics); Mice, Transgenic; Mice; Middle Age; Open Reading Frames;
Point Mutation; Polymorphism (Genetics); Prions [genetics] MT - Animal;
Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL
ARTICLE; REVIEW (122 references); REVIEW, ACADEMIC
The prion diseases, sometimes referred to as the "transmissible
spongiform encephalopathies," include kuru, Creutzfeldt-Jakob disease,
and Gerstmann-Straussler-Scheinker disease of humans as well as scrapie
and bovine spongiform encephalopathy of animals.
For many years, the prion
diseases were thought to be caused by viruses despite intriguing evidence
to the contrary.
The unique characteristic common to all of these disorders,
whether sporadic, dominantly inherited, or acquired by infection, is that
they involve the aberrant metabolism of the prion protein (PrP).
In many
cases, the cellular prion protein is converted into the scrapie isoform
by a posttranslational process that involves a conformational change.
Often,
the human prion diseases are transmissible to experimental animals and
all of the inherited prion diseases segregate with PrP gene mutations.
EM - 9407
IS - 0364-5134 LA - English
UI - 94206007 RN - 0 (Prions) ID - NS14069-NS-NINDS;
AG08967-AG-NIA; AG02132-AG-NIA; +
Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism
Proc Natl Acad Sci USA 1994 Mar 29;91(7):2839-42
Monari L; Chen SG; Brown P; Parchi P; Petersen RB;
Mikol J; Gray F; Cortelli P; Montagna P; Ghetti B; et al
Division of Neuropathology, Case Western Reserve University,
Cleveland, OH 44106. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Insomnia
[genetics]; Polymorphism (Genetics); Prion Diseases [genetics]; Prions
[genetics] MN - Codon; Peptide Fragments [chemistry]; Phenotype; Prions
[chemistry] [drug effects]; Serine Proteinases [metabolism] MT - Comparative
Study; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT -
JOURNAL ARTICLE
Fatal familial insomnia and a subtype of Creutzfeldt-Jakob
disease, two clinically and pathologically distinct diseases, are linked
to the same mutation at codon 178 (Asp-178-- Asn).
But segregate with different
genotypes determined by this mutation and the methionine-valine polymorphism
at codon 129 of the prion protein gene.
The abnormal isoforms of the prion
protein in these two diseases were found to differ both in the relative
abundance of glycosylated forms and in the size of the protease-resistant
fragments.
The size difference was consistent with a different protease
cleavage site, suggesting a different conformation of the protease-resistant
prion protein present in the two diseases.
These differences are likely
to be responsible for the type and location of the lesions that characterize
these two diseases.
Therefore, the combination of the mutation at codon
178 and the polymorphism at codon 129 determines the disease phenotype
by producing two altered conformations of the prion protein.
EM - 9407
IS - 0027-8424 LA - English
UI - 94195837 RN - EC 3.4.21 (Serine Proteinases);
EC 3.4.21.- (Tritirachium alkaline proteinase); 0 (Codon); 0 (Peptide Fragments);
0 (Prions); 0 (PrPSc Proteins) ID - NS-14509-NS-NINDS; NS-29822-NS-NINDS;
AG-08012-AG-NIA; +
Japanese family with Creutzfeldt-Jakob disease with codon 200 point mutation of the prion protein gene
Neurology 1994 Feb;44(2):299-301
Inoue I; Kitamoto T; Doh-ura K; Shii H; Goto I; Tateishi
J
Department of Neurology, Kokura-kinen Hospital, Kitakyusyu,
Japan. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Point Mutation; Prions
[genetics] MN - Adolescence; Adult; Cerebellum [metabolism] [pathology];
Codon; Creutzfeldt-Jakob Syndrome [pathology]; DNA [blood]; Deoxyribonucleases,
Type II Site-Specific; Immunohistochemistry; Japan; Lymphocytes [metabolism];
Lysine; Middle Age; Pedigree; Polymerase Chain Reaction; Prions [analysis];
Variation (Genetics) MT - Case Report; Female; Human; Male; Support, Non-U.S.
Gov't PT - JOURNAL ARTICLE
We report the first Japanese case of familial Creutzfeldt-Jakob
disease (CJD) with the heterozygous point mutation at codon 200 of the
prion protein gene. This suggests that the mutation is not race-specific.
The clinical and pathologic features of this case are not different from
those of sporadic CJD without point mutations. Some healthy members of
the family also carry the same mutation in the autosomal dominant inheritance
expression.
EM - 9405
IS - 0028-3878 LA - English
UI - 94142912 RN - EC 3.1.21.- (endodeoxyribonuclease
BsmAI); EC 3.1.21.4 (Deoxyribonucleases, Type II Site-Specific); 0 (Codon);
0 (Prions); 0 (PrPSc Proteins); 56-87-1 (Lysine); 9007-49-2 (DNA)
Prion protein (PrP) is not involved in the PathoGenesis of spongiform encephalopathy in zitter rats
NeuroSci Lett 1994 Jan 31;166(2):171-4
Gomi H; Ikeda T; Kunieda T; Itohara S; Prusiner SB;
Yamanouchi K
Institute for Virus Research, Kyoto University, Japan.
MJ - Prion Diseases [metabolism]; Prions [metabolism] MN - Amino Acid Sequence;
Base Sequence; Blotting, Southern; Blotting, Western; Brain [pathology];
Molecular Sequence Data; Open Reading Frames; Polymerase Chain Reaction;
Polymorphism, Restriction Fragment Length; Prion Diseases [genetics]; Rats,
Mutant Strains; Rats, Sprague-Dawley; Rats MT - Animal; Support, Non-U.S.
Gov't PT - JOURNAL ARTICLE
In order to elucidate the relationship between the
prion protein (PrP) structure and the development of spongiform encephalopathy
in zitter rats.
We analyzed the nucleotide sequences and restriction fragment
length variation (RFLV) of the Prn gene encoding PrP in zitter rats and
inbred SD/J rats as a control.
Prn genes from two strains had identical
nucleotide sequences in their coding sequences. Obvious RFLV on the locus
was not detected in zitter rats by a Southern blot hybridization. Consistently,
zitter rat brains express the normal cellular PrP (PrPC), but do not accumulate
the protease-resistant modified isoform (PrPSC).
These results indicate
that PrP is not involved in the PathoGenesis of spongiform encephalopathy
in zitter rats.
EM - 9408
IS - 0304-3940 LA - English
UI - 94232539 RN - 0 (Prions) SI - GENBANK/S69654
Insights into the role of the immune system in prion diseases
Proc Natl Acad Sci USA 1994 Jan 18;91(2):429-32
Berg LJ
Department of Cellular and Developmental Biology,
Harvard University, Cambridge, MA 02138. MJ - Prion Diseases [Immunology]
MN - Immune Tolerance; Prion Diseases [etiology] [transmission]; Prions
[genetics] [Immunology] [Pathogenicity]; Scrapie [etiology] [Immunology]
MT - Animal; Human PT - JOURNAL ARTICLE; REVIEW (26 references); REVIEW,
TUTORIAL EM - 9404
IS - 0027-8424 LA - English
UI - 94119899 RN - 0 (Prions); 0 (PrPSc Proteins)
Frontal lobe dementia is not a variant of prion disease
NeuroSci Lett 1993 Dec 24;164(1-2):1-4
Clinton J; Mann DM; Roberts GW
Department of Anatomy and Cell Biology, St. Mary's
Hospital Medical School, Imperial College, London, UK. MJ - Dementia [pathology];
Frontal Lobe [pathology]; Prion Diseases [pathology] MN - Aged, 80 and
over; Aged; Alzheimer's Disease [pathology]; Amyloid beta-Protein [Immunology]
[metabolism]; Cerebellum [pathology]; Immunohistochemistry; Middle Age;
Tissue Fixation MT - Female; Human; Male; Support, Non-U.S. Gov't PT -
JOURNAL ARTICLE
Frontal lobe dementia (FLD) is a syndromal diagnosis
with a variable pathology.
It has been argued that FLD is a dementing disorder
which should be nosologically and etiologically distinguished from other
types of dementia.
However, similarities with prior disease and Alzheimer's
disease have led to the suggestion that FLD is a variant of one or other
of these dementias.
We have tested this line of argument by examining the
frontal cortex and cerebellum of 14 FLD cases and probing the molecular
pathology using well characterized antibodies to prion protein and beta-amyloid
protein.
No prion protein deposits or significant levels of beta-amyloid
protein were detected. FLD is a dementing disorder whose molecular pathology,
whilst as yet uncharacterised, can be distinguished from those of other
dementing disorders.
EM - 9407
IS - 0304-3940 LA - English
UI - 94203419 RN - 0 (Amyloid beta-Protein)
Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins
Proc Natl Acad Sci USA 1993 Dec 1;90(23):10962-6
Pan KM; Baldwin M; Nguyen J; Gasset M; Serban A; Groth
D; Mehlhorn I; Huang Z; Fletterick RJ; Cohen FE; et al
Department of Neurology, University of California,
San Francisco 94143. MJ - Prions [chemistry]; Scrapie [etiology] MN - Circular
Dichroism; Hamsters; Immunohistochemistry; Mesocricetus; Microscopy, Electron;
Prions [isolation & purification]; Protein Structure, Secondary; Spectroscopy,
Fourier Transform Infrared MT - Animal; Support, Non-U.S. Gov't; Support,
U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE
Prions are composed largely, if not entirely, of prion
protein (PrPSc in the case of scrapie).
Although the formation of PrPSc
from the cellular prion protein (PrPC) is a post-translational process,
no candidate chemical modification was identified, suggesting that a conformational
change features in PrPSc synthesis.
To assess this possibility, we purified
both PrPC and PrPSc by using nondenaturing procedures and determined the
secondary structure of each.
Fourier-transform infrared (FTIR) spectroscopy
demonstrated that PrPC has a high alpha-helix content (42%) and no beta-sheet
(3%), findings that were confirmed by circular dichroism measurements.
In contrast, the beta-sheet content of PrPSc was 43% and the alpha-helix
30% as measured by FTIR.
As determined in earlier studies, N-terminally
truncated PrPSc derived by limited proteolysis, designated PrP 27-30, has
an even higher beta-sheet content (54%) and a lower alpha-helix content
(21%).
Neither PrPC nor PrPSc formed aggregates detectable by electron
microscopy, while PrP 27-30 polymerized into rod-shaped amyloids.
While the foregoing findings argue that the conversion of alpha-helices into
beta-sheets underlies the formation of PrPSc, we cannot eliminate the possibility
that an undetected chemical modification of a small fraction of PrPSc initiates
this process.
Since PrPSc seems to be the only component of the "infectious"
prion particle, it is likely that this conformational transition is a fundamental
event in the propagation of prions.
EM - 9403
IS - 0027-8424 LA - English
UI - 94068524 RN - 0 (Prions); 0 (PrPSc Proteins)
An Israeli family with Gerstmann-Straussler-Scheinker disease manifesting the codon 102 mutation in the prion protein gene
Neurology 1993 Dec;43(12):2718-9
Goldhammer Y; Gabizon R; Meiner Z; Sadeh M
Department of Neurology, Chaim Sheba Medical Center,
Tel Hashomer, Israel. MJ - Codon; Gerstmann-Straussler Syndrome [ethnology]
[genetics]; Jews; Mutation; Prions [genetics] MN - Adult; DNA [genetics];
Israel; Pedigree; Polymerase Chain Reaction MT - Case Report; Female; Human
PT - JOURNAL ARTICLE
We report the first family among the Jewish population
in Israel with Gerstmann-Straussler-Scheinker disease.
A proline-for-leucine
substitution at the codon 102 of the prion protein (PrP) gene was demonstrated.
This mutation has been reported in families with the ataxic form of the
disease.
EM - 9403
IS - 0028-3878 LA - English
UI - 94077411 RN - 0 (Codon); 0 (Prions); 0 (PrPSc
Proteins); 9007-49-2 (DNA)
A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease
Ann Neurol 1993 Dec;34(6):802-7
Pocchiari M; Salvatore M; Cutruzzola F; Genuardi M;
Allocatelli CT; Masullo C; Macchi G; Alema G; Galgani S; Xi YG; et al
Laboratory of Virology, Istituto Superiore di Sanita,
Rome, Italy. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Nerve Tissue Proteins
[genetics]; Point Mutation; Prions [genetics] MN - Aged, 80 and over; Aged;
Base Sequence; Middle Age; Molecular Sequence Data; Open Reading Frames
[genetics]; Pedigree MT - Female; Human; Male; Support, Non-U.S. Gov't
PT - JOURNAL ARTICLE
Complete sequencing of the prion protein open reading
frame of a 68-year-old woman affected by a familial form of Creutzfeldt-Jakob
disease (CJD) revealed a new mutation at codon 210 resulting in the substitution
of isoleucine for valine.
Moreover, a new 24-bp deletion encompassing codons
54 to 61 or 62 to 69 was found in the other allele. Four of the 17 asymptomatic
relatives tested carry the 210 mutation. Two of them were 81 and 82 years
old.
Four of 22 patients with CJD whose recorded familial history was negative
for demented illnesses, but none of 103 healthy control subjects, tested
positive for the 210 mutation.
These data suggest that the 210 mutation
is associated with CJD, but that environmental factors or incomplete penetrance
may contribute to the development of the disease. This finding also suggests
that in Italy, familial CJD is more common than previously reported.
EM
- 9403
IS - 0364-5134 LA - English
UI - 94071412 RN - 0 (Nerve Tissue Proteins); 0 (Prions);
0 (PrPSc Proteins)
A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesis
Ann Neurol 1993 Dec;34(6):808-13
Kitamoto T; Amano N; Terao Y; Nakazato Y; Isshiki
T; Mizutani T; Tateishi J
Department of Neuropathology, Kyushu University, Fukuoka,
Japan. MJ - Paraplegia [genetics]; Point Mutation; Prion Diseases [genetics]
MN - Adult; Base Sequence; Brain [pathology]; Codon [genetics]; Middle
Age; Molecular Sequence Data; Paraplegia [pathology] [physiopathology];
Prion Diseases [pathology] [physiopathology]; Spinal Cord [pathology] MT
- Female; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE
We report the clinicopathological findings of 5 patients
with an inherited prion disease with a codon 105 (Pro to Leu) mutation.
All of the patients had a spastic gait disturbance and progressive dementia
without either cerebellar signs, myoclonus, or periodic synchronous discharges.
Autopsy of 3 patients revealed numerous amyloid plaques in the cerebral
cortex, especially in the motor cortex and the frontal lobe where neuronal
loss and severe gliosis were observed in the absence of spongiform changes.
The cerebellum was preserved histologically except for only a few amyloid
plaques.
The pyramidal tracts in the brainstem and spinal cord showed vacuolated
changes and a loss of myelin, but no prion protein accumulations.
Thus,
the prion protein codon 105 mutation is considered to correspond to a new
variant of the Gerstmann-Straussler syndrome with spastic paraparesis.
EM - 9403
IS - 0364-5134 LA - English
UI - 94071413 RN - 0 (Codon) |