Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion proteinJ Biol Chem 1996 May 24;271(21):12661-8 Petersen RB; Parchi P; Richardson SL; Urig CB; Gambetti P Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. rbp@po.cwru.edu. MJ - Codon; Mutation; Polymorphism (Genetics); Prions [metabolism] MN - Base Sequence; Biological Transport; Brain [metabolism]; Cell Compartmentation; DNA Primers; Glycosylation; Molecular Sequence Data; Prion Diseases [genetics] [metabolism]; Prions [genetics]; Tumor Cells, Cultured MT - Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE Prion diseases are thought to be caused by the conversion of the normal, or cellular, prion protein (PrPC)(PrPres). There are three familial forms of human prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced age despite the congenital presence of the mutant prion protein (PrPM). The cellular mechanisms that result in the age-dependent conversion of PrPM into PrPres and the unique phenotypes associated with each PrPM are unknown. FFI and a familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N mutation results in instability of the mutant PrP which is partially corrected by N-glycosylation. Hence, only the glycosylated forms of PrPM reach the cell surface whereas the unglycosylated PrPM is also under-represented in the brain of FFI patients validating the cell model. These results offer new insight into the effect of the D178N mutation on the metabolism of the prion protein. EM - 9609 IS - 0021-9258 LA - English UI - 96218196 RN - 0 (Codon); 0 (DNA Primers); 0 (Prions) ID - AG-08992-AG-NIA; AG-08155-AG-NIA Hippocampal slices from prion protein null mice: disrupted Ca(2+)-activated K+ currentsNeuroSci Lett 1996 May 3;209(1):49-52 Colling SB; Collinge J; Jefferys JG Department of Physiology and Biophysics, St Mary's Hospital Medical School, Imperial College, London, UK. MJ - Calcium [pharmacology]; Hippocampus [physiology]; Potassium Channels [physiology]; Prions [genetics]; Pyramidal Cells [physiology] MN - Action Potentials; Analysis of Variance; Charybdotoxin [pharmacology]; Crosses, Genetic; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mice; Potassium Channels [drug effects]; Pyramidal Cells [drug effects]; Recombination, Genetic MT - Animal; Female; In Vitro; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE The intrinsic properties of hippocampal CA1 pyramidal cells were examined in mice lacking prion protein (PrP-null). The resting potentials, time constants, amplitude of the medium afterhyperpolarization (AHP) and spike firing accommodation did not differ from the control group. The PrP-null group differed in having lower input resistances, a lack of the late AHP and of a charybdotoxin-sensitive summated AHP. We propose that CA(2+)-activated K+ currents, in particular IAHP, are disrupted in PrP-null mice. EM - 9612 IS - 0304-3940 LA - English UI - 96322495 RN - 0 (Potassium Channels); 0 (Prions); 115422-61-2 (Charybdotoxin); 7440-70-2 (Calcium) ImmunoHistoChemical Detection Of Prion Protein In Lymphoid Tissues Of Sheep With Natural ScrapieVan Keulen LJ; Schreuder BE; Meloen RH; Mooij-Harkes G; Vromans ME; Langeveld JPIS - 0095-1137 LA - English UI - 96284431 RN - 0 (Antibodies); 0 (PrPSc Proteins) IS - 0028-0836 LA - English UI - 96186816 RN - 0 (Prions) IS - 0028-0836 LA - English UI - 96195059 RN - EC 4.1.1.15 (Glutamate Decarboxylase); 0 (Prions) IS - 0028-0836 LA - English UI - 96176245 RN - 0 (prion protein (106-126); 0 (Neurotoxins); 0 (Peptide Fragments); 0 (Prions); 0 (PrPC Proteins); 2666-93-5 (leucine methyl ester); 7005-03-0 (Leucine) IS - 0027-8424 LA - English UI - 96197325 RN - 0 (Prions) |
A prion disease with a novel 96-base pair insertional mutation in the prion protein geneNeurology 1996 Mar;46(3):761-6 Campbell TA; Palmer MS; Will RG; Gibb WR; Luthert PJ; Collinge J Prion Disease Group, Department of Biochemistry and Molecular Genetics, St. Mary's Hospital Medical School, London, UK. MJ - DNA Insertion Elements; Mutation; Prion Diseases [genetics]; Prions [genetics] MN - Amino Acid Sequence; Base Composition; Base Sequence; Brain [pathology]; DNA [genetics]; Middle Age; Molecular Probes [genetics]; Molecular Sequence Data; Prion Diseases [pathology] MT - Case Report; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE There are coding mutations in the prion protein gene
in familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker
disease, and other phenotypes that make up the inherited prion diseases.
Insertional mutations consisting of two, five, six, seven, eight, and nine
additional octapeptide repeat elements are seen in the inherited prion
diseases and usually present as atypical dementias with considerable intrafamilial
phenotypic variability. A four-octarepeat insertion was reported previously
in an individual without neurodegenerative disease who died of hepatic
cirrhosis. Here we report a novel four-octarepeat insertional mutation
in a case with classical clinical, electroencephalographic and histopathologic
features of CJD with the unusual finding of pronounced prion protein Immunoreactivity
of the molecular layer of the cerebellum. EM - 9608 Normal host prion protein necessary for scrapie-induced neurotoxicityNature 1996 Jan 25;379(6563):339-43 Brandner S; Isenmann S; Raeber A; Fischer M; Sailer A; Kobayashi Y; Marino S; Weissmann C; Aguzzi A Department of Pathology, University Hospital, Zurich, Switzerland. MJ - PrPC Proteins [metabolism]; PrPSc Proteins [toxicity]; Scrapie [etiology] MN - Brain Tissue Transplantation; Brain [metabolism] [pathology]; Immunoenzyme Techniques; Mice, Transgenic; Mice; PrPC Proteins [genetics]; PrPSc Proteins [metabolism]; Scrapie [metabolism] [pathology] MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Accumulation of the prion protein PrPSc, a pathological
and protease-resistant isoform of the normal host protein PrPC, is a feature
of prion disease such as scrapie. It is still unknown whether scrapie pathology
comes about by neurotoxicity of PrPSc, acute depletion of PrPC, or some
other mechanism. Here we investigate this question by grafting neural tissue
overexpressing PrPC into the brain of PrP-deficient mice which are scrapie-resistant
and do not propagate infectivity. After intracerebral inoculation with
scrapie prions, the grafts accumulated high levels of PrPSc and infectivity
and developed the severe histopathological changes characteristic of scrapie.
Moreover, substantial amounts of graft-derived PrPSc migrated into the
host brain. Even 16 months after inoculation no pathological changes were
seen in PrP-deficient tissue, not even in the immediate vicinity of the
grafts. Therefore, in addition to being resistant to scrapie infection,
brain tissue devoid of PrPC is not damaged by exogenous PrPSc. EM - 9604 Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNPProc Natl Acad Sci USA 1996 Jan 23;93(2):744-8 Ghetti B; Piccardo P; Spillantini MG; Ichimiya Y; Porro M; Perini F; Kitamoto T; Tateishi J; Seiler C; Frangione B; Bugiani O; Giaccone G; Prelli F; Goedert M; Dlouhy SR; Tagliavini F Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis 46202-5120, USA. MJ - Cerebral Amyloid Angiopathy [pathology]; Dementia [etiology]; Mutation; Prions [genetics] MN - Adult; Amyloid [chemistry]; Blood Vessels [pathology]; Cerebral Cortex [pathology]; Japan [ethnology]; Neurons [pathology]; Phenotype; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Prions [Immunology] MT - Case Report; Female; Human; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE Deposition of PrP amyloid in cerebral vessels in conjunction
with neurofibrillary lesions is the NeuroPathologic hallmark of the dementia
associated with a stop mutation at codon 145 of PRNP, the gene encoding
the prion protein (PrP). In this disorder, the vascular amyloid in tissue
sections and the approximately 7.5-kDa fragment extracted from amyloid
are labeled by antibodies to epitopes located in the PrP sequence including
amino acids 90-147. Amyloid-laden vessels are also labeled by antibodies
against the C terminus, suggesting that PrP from the normal allele is involved
in the pathologic process. Abundant neurofibrillary lesions are present
in the cerebral gray matter. They are composed of paired helical filaments,
are labeled with antibodies that recognize multiple phosphorylation sites
in tau protein, and are similar to those observed in Alzheimer disease.
A PrP cerebral amyloid angiopathy has not been reported in diseases caused
by PRNP mutations or in human transmissible spongiform encephalopathies;
we propose to name this phenotype PrP cerebral amyloid angiopathy (PrP-CAA).
EM - 9605 Mutant and infectious prion proteins display common biochemical properties in cultured cellsJ Biol Chem 1996 Jan 19;271(3):1633-7 Lehmann S; Harris DA Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. MJ - Point Mutation; Prions [metabolism] MN - Amino Acid Sequence; CHO Cells; Cell Line; Cell Membrane [metabolism]; Detergents; Hamsters; Mice; Neuroblastoma; Peptide Peptidohydrolases [metabolism]; Phenotype; Phospholipase C [metabolism]; PrPSc Proteins [biosynthesis] [isolation & purification] [metabolism]; Prions [biosynthesis] [isolation & purification]; Recombinant Proteins [biosynthesis] [metabolism]; Solubility; Transfection; Tumor Cells, Cultured MT - Animal; Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Prion diseases are unusual neurodegenerative disorders
that can be both infectious and inherited. Both forms are hypothesized
to result from a posttranslational structural alteration in the cell surface
glycoprotein PrPc (cellular isoform of the prion protein) that converts
it into the protease-resistant isoform PrPSc (scrapie isoform of the prion
protein). However, a direct comparison of molecular events underlying these
two manifestations of prion diseases has not been possible, because there
has been no cell culture model for the familial forms. We report here that
when mutant prion proteins associated with three different inherited prion
disorders of humans are expressed as their murine homologues in cultured
Chinese hamster ovary cells, the proteins are protease-resistant and detergent-insoluble,
two biochemical properties characteristic of infectious PrPSc. In addition,
each mutant protein remains tightly associated with the plasma membrane
after enzymatic cleavage of its glycosylphosphatidylinositol anchor, a
property that we now show is also typical of infectious PrPSc. The cell
culture system described here is the first in vitro model for familial
prion diseases and provides compelling evidence that infectious and genetic
cases share common molecular features. EM - 9605 Unaltered susceptibility to BSE in transgenic mice expressing human prion protein[see comments] CM - Comment in: Nature 1995 Dec 21-28; 378(6559):759Nature 1995 Dec 21-28;378(6559):779-83 Collinge J; Palmer MS; Sidle KC; Hill AF; Gowland I; Meads J; Asante E; Bradley R; Doey LJ; Lantos PL Department of Biochemistry and Molecular Genetics, Imperial College School of Medicine at St Mary's, London, UK. MJ - Encephalopathy, Bovine Spongiform [transmission]; Prions [biosynthesis] MN - Brain [metabolism]; Cattle; Creutzfeldt-Jakob Syndrome [transmission]; Disease Susceptibility; Mice, Inbred C57BL; Mice, Transgenic; Mice; PrPSc Proteins [biosynthesis]; Recombinant Proteins; Species Specificity MT - Animal; Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Prion diseases are transmissible neurodegenerative
conditions of humans and animals. Prions consist principally of a post-translationally
modified form of prion protein (PrP), PrP(Sc), which is partly protease
resistant. Transmission of prion diseases between species is limited by
a 'species barrier' determined in part by the degree of sequence homology
between host PrP and inoculated PrP(Sc) (ref.3) and by prion strain type.
The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom
and other countries has led to concerns that transmission to humans may
occur by dietary exposure. BSE appears to be caused by a single strain,
distinct from those of natural or experimental scrapie, which is also seen
in the new prion diseases of cats and ruminants that have presumably arisen
from dietary BSE exposure. Here we show that transgenic mice expressing
human PrP in addition to mouse PrP can generate human PrP(Sc) and 'human'
prions. These mice therefore provide a model to study experimentally the
species barrier limiting BSE transmission to humans. Incubation periods
to BSE in transgenic mice are not shortened by expression of human PrP,
and only mouse PrP(Sc) is produced in response to such challenge. EM -
9603 Hypokinesia and presenile dementia in a Dutch family with a novel insertion in the prion protein geneBrain 1995 Dec;118 ( Pt 6):1565-71 van Gool WA; Hensels GW; Hoogerwaard EM; Wiezer JH; Wesseling P; Bolhuis PA Department of Neurology, University of Amsterdam, The Netherlands. MJ - DNA Insertion Elements; Dementia, Presenile [genetics]; Hypokinesia [genetics]; Prion Diseases [genetics] [metabolism]; Prions [genetics] MN - Adult; Base Sequence; Brain [metabolism] [pathology]; Dementia, Presenile [metabolism] [pathology]; Genetics, Biochemical; Middle Age; Molecular Sequence Data; Pedigree; Prion Diseases [pathology]; Prions [metabolism] MT - Case Report; Female; Human; Male PT - JOURNAL ARTICLE The clinical features and disease course of six patients
from a family with autosomal dominant inheritance of presenile dementia
and a hypokinetic syndrome are described. In the past, these patients have
carried diagnoses of Pick's disease, Huntington's disease, Parkinson-dementia,
and one patient was described as suffering from a 'peculiar type of presenile
dementia' in a case report. In the two cases examined, the most distinctive
NeuroPathological features were extensive globular deposits of periodic
acid-Schiff plus diastase (PAS)-positive material, having tinctural properties
of amyloid only to a limited degree, in the cerebellum and cerebral cortex.
These globules stained positively with antibodies against prion protein.
Southern blot of MspI-digested genomic DNA showed an abnormal band of approximately
950 bp in all three patients from which material was available. Direct
sequencing of the abnormal allele revealed an insert consisting of eight
extra 24-nucleotide repeats in the patients, which was absent in a healthy
first degree relative who was considered well beyond the age of onset of
symptoms in this family. The nucleotide sequence of the abnormal insert
of 192 bp was different from that of a previously described insert of equal
length. Adding to previous descriptions of mutations in the prion protein
gene, this report emphasizes the clinical, NeuroPathological and genetic
Heterogeneity of inherited prion disease. EM - 9606 Prion disease (PrP-A117V) presenting with ataxia instead of dementiaNeurology 1995 Nov;45(11):2042-50 Mastrianni JA; Curtis MT; Oberholtzer JC; Da Costa MM; De Armond S; Prusiner SB; Garbern JY Department of Neurology, University of California, San Francisco 94143-0518, USA. MJ - Ataxia [physiopathology]; Prion Diseases [genetics] [physiopathology] MN - Adult; Base Sequence; DNA [analysis]; Dementia [physiopathology]; Immunohistochemistry; Magnetic Resonance Imaging; Molecular Sequence Data; Polymerase Chain Reaction; Prion Diseases [pathology] MT - Case Report; Human; Male; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE Gerstmann-Straussler-Scheinker disease (GSS) is caused
by several different point mutations of the prion protein (PrP) gene, each
of which generally produces a distinct clinical phenotype. An ataxic form
of GSS is genetically linked to a mutation at codon 102 (CCG-- CTG) leading
to the substitution of leucine for proline, while a "telencephalic" variant
of GSS, in which dementia is the predominant symptom and ataxia is minimal,
has been described in two kindreds with a mutation at codon 117 (GCA--
GTG) resulting in the substitution of valine for alanine. In this report,
we present a family with ataxic GSS that has, however, the same mutation
at codon 117 as is present in the telencephalic variant of GSS. Other than
an additional silent mutation (GCA-- GCG) at codon 117 on the normal allele,
there were no other mutations detected. At the polymorphic codon 129, valine
was encoded by both alleles in the proband that we studied. Why this family
with prion disease (PrP-A117V) should present with ataxia instead of dementia,
which was found in two previously identified families with the same PrP
gene mutation, remains to be established. EM - 9603 Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cellsScience 1995 Oct 6;270(5233):93-5 Masison DC; Wickner RB Section on Genetics of Simple Eukaryotes, National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD 20892-0830, USA. MJ - Fungal Proteins [genetics]; Prions [genetics]; Saccharomyces cerevisiae [genetics] MN - Amino Acid Sequence; Base Sequence; Fungal Proteins [chemistry] [metabolism]; Genes, Fungal; Genetic Complementation Test; Molecular Sequence Data; Nitrogen [metabolism]; Plasmids; Prions [metabolism]; Promoter Regions (Genetics); Saccharomyces cerevisiae [chemistry] [metabolism]; Sequence Deletion; Serine Proteinases [metabolism] PT - JOURNAL ARTICLE The genetic properties of the [URE3] non-Mendelian
element of Saccharomyces cerevisiae suggest that it is a prion (infectious
protein) form of Ure2p, a regulator of nitrogen catabolism. In extracts
from [URE3] strains, Ure2p was partially resistant to proteinase K compared
with Ure2p from wild-type extracts. Overexpression of Ure2p in wild-type
strains induced a 20- to 200-fold increase in the frequency with which
[URE3] arose. Overexpression of just the amino-terminal 65 residues of
Ure2p increased the frequency of [URE3] induction 6000-fold. Without this
"prion-inducing domain" the carboxyl-terminal domain performed the nitrogen
regulation function of Ure2p, but could not be changed to the [URE3] prion
state. Thus, this domain induced the prion state in trans, whereas in cis
it conferred susceptibility of the adjoining nitrogen regulatory domain
to prion infections. EM - 9601 Prion protein isoforms, a convergence of biological and structural investigationsJ Biol Chem 1995 Aug 18;270(33):19197-200 Baldwin MA; Cohen FE; Prusiner SB Department of Neurology, University of California, San Francisco 94143-0518, USA. MJ - Prions [chemistry] [metabolism] MN - Models, Molecular; Prions [Pathogenicity]; Slow Virus Diseases [genetics]; Spectrum Analysis; Structure-Activity Relationship; Zoonoses MT - Animal; Human PT - JOURNAL ARTICLE; REVIEW (80 references); REVIEW, TUTORIAL EM - 9511 IS - 0021-9258 LA - English UI - 95370242 RN - 0 (Prions) Truncated forms of the human prion protein in normal brain and in prion diseasesJ Biol Chem 1995 Aug 11;270(32):19173-80 Chen SG; Teplow DB; Parchi P; Teller JK; Gambetti P; Autilio-Gambetti L Division of Neuropathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. MJ - Brain Chemistry; Prion Diseases [metabolism]; Prions [analysis] MN - Adult; Aged, 80 and over; Aged; Amino Acid Sequence; Middle Age; Molecular Sequence Data; Neuroblastoma [chemistry]; Peptide Fragments [analysis]; Prions [chemistry]; Tumor Cells, Cultured MT - Human; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE The cellular form of the prion protein (PrPc) is a
glycoprotein anchored to the cell membrane by a glycosylphosphatidylinositol
moiety. An aberrant form of PrPc that is partially resistant to proteases,
PrPres, is a hallmark of prion diseases, which in humans include Cruetzfeldt-Jakob
disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial
insomnia. We have characterized the major forms of PrP in normal and pathological
human brains. A COOH-terminal fragment of PrPc, designated C1, is abundant
in normal and CJD brains as well as in human neuroblastoma cells. Sequence
analysis revealed that C1 contains alternative NH2 termini starting at
His-111 or Met-112. Like PrPc, C1 is glycosylated, anchored to the cell
membrane, and is heat-stable. Consistent with the lack of the NH2-terminal
region of PrPc, C1 is more acidic than PrPc and does not bind heparin.
An additional fragment longer than C1, designated C2, is present in substantial
amounts in CJD brains. Like PrPres, C2 is resistant to proteases and is
detergent-insoluble. Our data indicate that C1 is a major product of normal
PrPc metabolism, generated by a cleavage that disrupts the neurotoxic and
amyloidogenic region of PrP comprising residues 106-126. This region remains
intact in C2, suggesting a role for C2 in prion diseases. EM - 9511 The abnormal isoform of the prion protein accumulates in late-endosome-like organelles in scrapie-infected mouse brainJ Pathol 1995 Aug;176(4):403-11 Arnold JE; Tipler C; Laszlo L; Hope J; Landon M; Mayer RJ Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, U.K. MJ - Brain [metabolism]; Endosomes [metabolism]; Prions [metabolism]; Scrapie [metabolism] MN - Blotting, Western; Brain [ultrastructure]; Mice, Inbred C57BL; Mice; Microscopy, Electron; Prions [chemistry]; Scrapie [pathology] MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE The prion encephalopathies are characterized by accumulation
in the brain of the abnormal form PrPsc of a normal host gene product PrPc.
The mechanism and site of formation of PrPsc from PrPc are currently unknown.
In this study, ME7 scrapie-infected mouse brain was used to show, both
biochemically and by double-labelled Immunogold electron microscopy, that
proteinase K-resistant PrPsc is enriched in subcellular structures which
contain the cation-independent mannose 6-phosphate receptor, ubiquitin-protein
conjugates, beta-glucuronidase, and cathepsin B, termed late endosome-like
organelles. The glycosylinositol phospholipid membrane-anchored PrPc will
enter such compartment for normal degradation and the organelles may therefore
act as chambers for the conversion of PrPc into infectious PrPsc in this
murine model of scrapie. EM - 9601 Regional distribution of protease-resistant prion protein in fatal familial insomniaAnn Neurol 1995 Jul;38(1):21-9 Parchi P; Castellani R; Cortelli P; Montagna P; Chen SG; Petersen RB; Manetto V; Vnencak-Jones CL; McLean MJ; Sheller JR; et al Division of Neuropathology, Case Western Reserve University, Cleveland, OH 44106-4901, USA. MJ - Brain Chemistry; Insomnia; Prion Diseases [pathology]; Prions [analysis] MN - Adult; Glial Fibrillary Acidic Protein [analysis]; Immunoblotting; Insomnia [genetics] [pathology]; Middle Age; Peptide Peptidohydrolases [metabolism]; PrPC Proteins [analysis] MT - Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE Protease-resistant prion protein, total prion protein,
and glial fibrillary acidic protein were measured in various brain regions
from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine
at codon 129 (mean duration, 10.7 +/- 4 months) and 3 were heterozygotes
methionine/valine (mean duration, 23 +/- 11 months). In all subjects, protease-resistant
prion protein was detected in gray matter but not in white matter and peripheral
organs. Its distribution was more widespread than that of the histopathological
lesions, which were observed only in the presence of a critical amount
of the abnormal protein. In the mediodorsal thalamic nucleus, however,
a severe neuronal loss and astrogliosis were associated with relatively
moderate amounts of protease-resistant prion protein, suggesting a higher
vulnerability. There was no overall correlation between amount of protease-resistant
prion protein and either glial fibrillary acidic protein or total prion
protein. While protease-resistant prion protein was virtually limited to
subcortical areas and showed a selective pattern of distribution in the
subjects with disease of the shortest duration, it was more widespread
in the subjects with a longer clinical course, indicating that with time
the disease process spreads within the brain. The kinetics of the accumulation
of protease-resistant prion protein varied among different brain regions:
While in the neocortex and to a lesser extent in the limbic lobe and in
the caudate nucleus, the amount increased with disease duration, in the
mediodorsal thalamic nucleus and in the brainstem it was present in comparable
amounts in all subjects regardless of the disease duration.(ABSTRACT TRUNCATED
AT 250 WORDS). EM - 9510 Non-genetic propagation of strain-specific properties of scrapie prion protein[see comments] CM - Comment in: Nature 1995 Jun 22; 375(6533):628-9Nature 1995 Jun 22;375(6533):698-700 Bessen RA; Kocisko DA; Raymond GJ; Nandan S; Lansbury PT; Caughey B Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA. MJ - PrPC Proteins [metabolism]; PrPSc Proteins [metabolism]; Prions [metabolism] MN - Cetylpyridinium [pharmacology]; Guanidines [pharmacology]; Hamsters; Mesocricetus; PrPC Proteins [chemistry]; PrPSc Proteins [chemistry]; Prion Diseases [metabolism]; Prions [classification]; Serine Proteinases [metabolism]; Species Specificity; Tissue Culture MT - Animal PT - JOURNAL ARTICLE The infectious agents causing scrapie and other transmissible
spongiform encephalopathies have been postulated to consist solely of the
protease-resistant form of prion protein (PrPSc). One unprecedented requirement
of the protein-only model is that the 'inheritance' of Pathogen strain
differences must be mediated by stable variations in PrPSc structure, rather
than mutations in an agent-specific nucleic acid. Strain differences in
PrPSc structure have been described for the hyper (HY) and drowsy (DY)
strains of hamster transmissible mink encephalopathy (TME), a scrapie-like
disease originating in mink. Although HY and DY PrPSc are both post-translationally
derived from the precursor prion protein (PrPC) they are cleaved at different
amino-terminal sites by proteinase K (ref. 8). Here we investigate whether
this strain-specific property of PrPSc is transmitted to PrPC during formation
of new PrPSc. PrPSc from the HY and DY TME strains converted the protease-sensitive
PrPC into two distinct sets of protease-resistant PrP products in a cell-free
system. These data provide evidence that self-propagation of PrPSc polymers
with distinct three-dimensional structures could be the molecular basis
of scrapie strains. EM - 9509 Prion diseases. Yielding under the strain[news; comment] CM - Comment on: Nature 1995 Jun 22; 375(6533):698-700Nature 1995 Jun 22;375(6533):628-9 Weissmann C MJ - Prion Diseases [virology]; Prions [genetics] MN - PrPC Proteins [chemistry] [genetics]; PrPSc Proteins [chemistry] [genetics]; Prions [chemistry]; Protein Folding MT - Animal; Human PT - COMMENT; NEWS EM - 9509 IS - 0028-0836 LA - English UI - 95312094 RN - 0 (Prions); 0 (PrPC Proteins); 0 (PrPSc Proteins) |
Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]Science 1995 May 12;268(5212):880-4 Chernoff YO; Lindquist SL; Ono B; Inge-Vechtomov SG; Liebman SW Department of Biological Sciences, University of Illinois, Chicago 60607-7020, USA. MJ - Fungal Proteins [biosynthesis]; Heat-Shock Proteins [physiology]; Prions [biosynthesis]; Saccharomyces cerevisiae [physiology] MN - Fungal Proteins [genetics] [physiology]; Gene Expression; Heat-Shock Proteins [genetics]; Mutation; Saccharomyces cerevisiae [genetics]; Suppression, Genetic MT - Support, Non-U.S. Gov't PT - JOURNAL ARTICLE The yeast non-Mendelian factor [psi+] has been suggested
to be a self-modified protein analogous to mammalian prions. Here it is
reported that an intermediate amount of the chaperone protein Hsp104 was
required for the propagation of the [psi+] factor. Over-production or inactivation
of Hsp104 caused the loss of [psi+]. These results suggest that chaperone
proteins play a role in prion-like phenomena, and that a certain level
of chaperone expression can cure cells of prions without affecting viability.
This may lead to antiprion treatments that involve the alteration of chaperone
amounts or activity. EM - 9508 Earthquakes and prions[letter]Fertil Steril 1995 May;63(5):1137-9 Otani T MJ - Creutzfeldt-Jakob Syndrome [transmission]; Drug Contamination; Fertilization in Vitro; Prions; Serum Albumin MT - Female; Human; Male PT - LETTER EM - 9507 IS - 0015-0282 LA - English UI - 95237448 RN - 0 (Prions); 0 (Serum Albumin) Species specificity in the cell-free conversion of prion protein to protease-resistant forms: a model for the scrapie species barrierProc Natl Acad Sci USA 1995 Apr 25;92(9):3923-7 Kocisko DA; Priola SA; Raymond GJ; Chesebro B; Lansbury PT Jr; Caughey B Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergies and Infectious Diseases, Hamilton, MT 59840,USA. MJ - Peptide Peptidohydrolases [metabolism]; Prions [metabolism]; Scrapie [metabolism] MN - Drug Resistance; Glycosylation; Hamsters; Mice, Inbred Strains; Mice; Models, Structural; Prions [chemistry] [drug effects]; Protein Processing, Post-Translational; Species Specificity; Tunicamycin [pharmacology] MT - Animal; Comparative Study PT - JOURNAL ARTICLE Scrapie is a transmissible neurodegenerative disease
that appears to result from an accumulation in the brain of an abnormal
protease-resistant isoform of prion protein (PrP) called PrPsc. Conversion
of the normal, protease-sensitive form of PrP (PrPc) to protease-resistant
forms like PrPsc has been demonstrated in a cell-free reaction composed
largely of hamster PrPc and PrPsc. We now report studies of the species
specificity of this cell-free reaction using mouse, hamster, and chimeric
PrP molecules. Combinations of hamster PrPc with hamster PrPsc and mouse
PrPc with mouse PrPsc resulted in the conversion of PrPc to protease-resistant
forms. Protease-resistant PrP species were also generated in the nonhomologous
reaction of hamster PrPc with mouse PrPsc, but little conversion was observed
in the reciprocal reaction. Glycosylation of the PrPc precursors was not
required for species specificity in the conversion reaction. The relative
conversion efficiencies correlated with the relative transmissibilities
of these strains of scrapie between mice and hamsters. Conversion experiments
performed with chimeric mouse/hamster PrPc precursors indicated that differences
between PrPc and PrPsc at residues 139, 155, and 170 affected the conversion
efficiency and the size of the resultant protease-resistant PrP species.
We conclude that there is species specificity in the cell-free interactions
that lead to the conversion of PrPc to protease-resistant forms. This specificity
may be the molecular basis for the barriers to interspecies transmission
of scrapie and other transmissible spongiform encephalopathies in vivo.
EM - 9508 Etiology and PathoGenesis of prion diseasesAm J Pathol 1995 Apr;146(4):785-811 De Armond SJ; Prusiner SB Department of Pathology, University of California, San Francisco, USA. MJ - Prion Diseases [etiology]; Prions [Pathogenicity] MN - Amino Acid Sequence; Molecular Sequence Data; Prion Diseases [genetics] [transmission]; Prions [genetics] MT - Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE; REVIEW (219 references); REVIEW, ACADEMIC EM - 9507 IS - 0002-9440 LA - English UI - 95233488 RN - 0 (Prions) ID - NS14069-NS-NINDS; AG08967-AG-NIA; AG02132-AG-NIA; + Scrapie prions selectively modify the stress response in neuroblastoma cellsProc Natl Acad Sci USA 1995 Mar 28;92(7):2944-8 Tatzelt J; Zuo J; Voellmy R; Scott M; Hartl U; Prusiner SB; Welch WJ Department of Neurology, University of California, San Francisco 94143, USA. MJ - DNA-Binding Proteins [biosynthesis]; Heat-Shock Proteins [biosynthesis]; Prions [metabolism]; Scrapie [virology] MN - Cell Line; DNA-Binding Proteins [analysis]; Heat-Shock Proteins [antagonists & inhibitors]; Heat; Mice; Neuroblastoma; Prions [biosynthesis]; Rats; Subcellular Fractions [metabolism]; Transcription Factors [biosynthesis]; Tumor Cells, Cultured MT - Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE The fundamental event underlying scrapie infection
seems to be a conformational change in the prion protein. To investigate
proteins that might feature in the conversion of the cellular prion protein
(PrPC) into the scrapie isoform (PrPSc), we examined mouse neuroblastoma
N2a cells for the expression and cellular distribution of heat shock proteins
(Hsps), some of which function as molecular chaperones. In scrapie-infected
N2a (ScN2a) cells, Hsp72 and Hsp28 were not induced by heat shock, sodium
arsenite, or an amino acid analog, in contrast to uninfected control N2a
cells, while other inducible Hsps were increased by these treatments. Following
heat shock of the N2a cells, constitutively expressed Hsp73 was translocated
from the cytoplasm into the nucleus and nucleolus. In contrast, the distribution
of Hsp73 in ScN2a cells was not altered by heat shock; the discrete cytoplasmic
structures containing Hsp73 were largely resistant to detergent extraction.
These alterations in the expression and subcellular translocation of specific
Hsps in ScN2a cells may reflect the cellular response to the accumulation
of PrPSc. Whether any of these Hsps feature in the conversion of PrPC into
PrPSc or the PathoGenesis of prion diseases remains to be established.
EM - 9507 Allelic variations in apolipoprotein E and prion protein genotype related to plaque formation and age of onset in sporadic Creutzfeldt-Jakob diseaseNeuroSci Lett 1995 Mar 3;187(2):127-9 Pickering-Brown SM; Mann DM; Owen F; Ironside JW; de Silva R; Roberts DA; Balderson DJ; Cooper PN Division of NeuroScience, School of Biological Sciences, University of Manchester, UK. MJ - Alleles; Apolipoproteins E [genetics]; Creutzfeldt-Jakob Syndrome [genetics] [pathology]; Prions [genetics] MN - Age of Onset; Aged; Genotype; Middle Age; Polymerase Chain Reaction; Polymorphism (Genetics) MT - Female; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Prion gene sequence is thought to affect the phenotypic
expression of prion disease and the E2 variant of apolipoprotein E (Apo
E) can be neuroprotective in dementia. We determined codon 129 of the prion
gene and the Apo E variants in Creutzfeldt-Jakob disease (CJD) using PCR
and restriction digest. We found a significant correlation between valine
at codon 129 of the prion protein gene and the presence of plaque in CJD
and a later age of onset in CJD cases possessing the Apo E2 allele. This
study provides further evidence that sequence variations in the prion gene
can modify disease pathology and the neuroprotection afforded by Apo E2
is not confined to Alzheimer's disease. EM - 9509 Developmental expression of the prion protein gene in glial cellsNeuron 1995 Mar;14(3):509-17 Moser M; Colello RJ; Pott U; Oesch B Brain Research Institute, University of Zurich, Switzerland. MJ - Aging [metabolism]; Brain [metabolism]; Corpus Callosum [metabolism]; Gene Expression; Neuroglia [physiology]; Optic Nerve [metabolism]; Prions [biosynthesis] MN - Astrocytes [metabolism]; Brain [growth & development]; Corpus Callosum [growth & development]; Hamsters; In Situ Hybridization; Mesocricetus; Neuroglia [metabolism]; Oligodendroglia [metabolism]; Optic Nerve [growth & development]; RNA Probes; RNA, Messenger [analysis] [biosynthesis]; Rats, Inbred Lew; Rats; X-Rays MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Replication of prions is dependent on the presence
of the host protein PrPc. During the course of disease, PrPc is converted
into an abnormal isoform, PrPSc, which accumulates in the brain. Attempts
to identify the cell type(s) in which prion replication and PrP conversion
occur have reached conflicting results. Although PrP mRNA is present in
high amounts in neurons throughout the life of the animal, PrPSc initially
accumulates in astrocytes and possibly other glial cells and, later in
the course of the disease, spreads diffusely in the tissue, often in white
matter. We report here that PrP mRNA is expressed not only in neurons but
also in astrocytes and oligodendrocytes throughout the brain of postnatal
hamsters and rats. The level of glial Prp mRNA expression in neonatal animals
was comparable to that of neurons and increased two-fold during postnatal
development. A substantial portion of brain PrP mRNA is therefore contributed
by glial cells. Our results provide an explanation for the accumulation
of PrPSc in white matter tissue and in the cytoplasm of glial cells and
argue for a direct involvement of glia in prion propagation. EM - 9507 Prion protein accumulation in the spinal cords of patients wih sporadic and growth hormone associated Creutzfeldt-Jakob diseaseNeuroSci Lett 1995 Jan 2;183(1-2):127-30 Goodbrand IA; Ironside JW; Nicolson D; Bell JE National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Edinburgh, UK. MJ - Creutzfeldt-Jakob Syndrome [pathology]; Somatotropin [metabolism]; Spinal Cord [pathology] MN - Antibodies [Immunology]; Autopsy; Immunohistochemistry; Prions MT - Human PT - JOURNAL ARTICLE An Immunohistological study of the spinal cord in 20
cases of sporadic and 4 iatrogenic (growth hormone) cases of Creutzfeldt-Jakob
(CJD) disease patients was performed to detect the presence of disease
specific prion protein using a number of different antisera. Prion protein
was present in all the growth hormone recipients and in 11 of the 20 sporadic
CJD cases. Plaque-like deposits of prion protein were found in all the
growth hormone cases and three of the sporadic cases. This is the first
demonstration of the topographic Immunolocalisation of prion protein in
the spinal cord of CJD patients, a feature which could help elucidate some
important aspects of the PathoGenesis of CJD. EM - 9508 Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prionsNeuron 1995 Jan;14(1):29-41 Gomi H; Yokoyama T; Fujimoto K; Ikeda T; Katoh A; Itoh T; Itohara S Institute for Virus Research, Kyoto University, Japan. MJ - Glial Fibrillary Acidic Protein [physiology]; Prions [metabolism]; Scrapie [etiology] MN - Astrocytes [pathology] [physiology]; Brain Chemistry; Brain [growth & development]; Gene Targeting; Glial Fibrillary Acidic Protein [genetics]; Mice, Inbred C57BL; Mice, Mutant Strains; Mice; Mutagenesis; RNA, Messenger [analysis]; Scrapie [pathology]; Spinal Cord [chemistry] [growth & development]; Vimentin [metabolism]; beta-Galactosidase [metabolism] MT - Animal; Female; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Glial fibrillary acidic protein (GFAP) is an intermediate
filament protein specifically expressed in astrocytes in the CNS. To examine
the function of GFAP in vivo, the Gfap gene was disrupted by gene targeting
in embryonic stem cells. Mice homozygous for the mutation were completely
devoid of GFAP but exhibited normal development and showed no obvious anatomical
abnormalities in the CNS. When inoculated with infectious scrapie prions,
the mutant mice exhibited NeuroPathological changes typical of prion diseases.
Infectious prions accumulated in brains of the mutant mice to a degree
similar to that in control littermates. These results suggest that GFAP
is not essential for the morphogenesis of the CNS or for astrocytic responses
against neuronal injury. The results argue against the hypothesis that
GFAP plays a crucial role in the PathoGenesis of prion diseases. EM - 9504 The prion diseasesSci Am 1995 Jan;272(1):48-51, 54-7 Prusiner SB University of California School of Medicine, San Francisco. MJ - Prion Diseases MN - Prion Diseases [etiology] [pathology]; Prions [genetics] [Pathogenicity] MT - Animal; Human PT - JOURNAL ARTICLE; REVIEW (6 references); REVIEW, TUTORIAL EM - 9504 IS - 0036-8733 LA - English UI - 95125423 RN - 0 (Prions) Inherited Creutzfeldt-Jakob disease in a British family associated with a novel 144 base pair insertion of the prion protein geneJ Neurol NeuroSurg Psychiatry 1995 Jan;58(1):65-9 Nicholl D; Windl O; de Silva R; Sawcer S; Dempster M; Ironside JW; Estibeiro JP; Yuill GM; Lathe R; Will RG North Manchester General Hospital, Crumpsall, UK. MJ - Creutzfeldt-Jakob Syndrome [genetics]; DNA Insertion Elements; Prions [genetics]; Proteins [genetics] MN - Base Sequence; Creutzfeldt-Jakob Syndrome [diagnosis] [physiopathology]; DNA Primers; Diagnosis, Differential; Genome, Human; Huntington's Disease [diagnosis] [physiopathology]; Middle Age; Molecular Sequence Data; Mutagenesis; Occipital Lobe [physiopathology] [ultrastructure]; Pedigree; Polymerase Chain Reaction; Prion Diseases [physiopathology]; Putamen [physiopathology] [ultrastructure] MT - Case Report; Comparative Study; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE A case of familial Creutzfeldt-Jakob disease associated
with a 144 base pair insertion in the open reading frame of the prion protein
gene is described. Sequencing of the mutated allele showed an arrangement
of six octapeptide repeats, distinct from that of a recently described
British family with an insertion of similar size. Thirteen years previously
the brother of the proband had died from "Huntington's disease", but re-examination
of his NeuroPathology revealed spongiform encephalopathy and anti-prion
protein Immunocytochemistry gave a positive result. The independent evolution
of at least two distinct pathological 144 base pair insertions in Britain
is proposed. The importance of maintaining a high index of suspicion of
inherited Creutzfeldt-Jakob disease in cases of familial neurodegenerative
disease is stressed. EM - 9504 Abnormal accumulation of prion protein mRNA in muscle fibers of patients with sporadic inclusion-body myositis and hereditary inclusion-body myopathy[see comments] CM - Comment in: Am J Pathol 1994 Dec; 145(6):1261-4Am J Pathol 1994 Dec;145(6):1280-4 Sarkozi E; Askanas V; Engel WK Department of Neurology, University of Southern California School of Medicine, Los Angeles. MJ - Inclusion Bodies [ultrastructure]; Muscle Fibers [metabolism]; Muscular Diseases [pathology]; Myositis [metabolism] [pathology]; Prions [genetics]; RNA, Messenger [metabolism] MN - Adult; Aged; Immunohistochemistry; In Situ Hybridization; Middle Age; Muscular Diseases [metabolism]; Prions [metabolism] MT - Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Sporadic inclusion-body myositis is the most common
progressive muscle disease of older patients. The muscle biopsy demonstrates
mononuclear cell inflammation and vacuolated muscle fibers containing paired
helical filaments and 6 to 10-nm fibrils, both resembling those of Alzheimer
brain, and Congo-red positivity. Hereditary inclusion-body myopathy designates
patients cytopathologically similar but without inflammation. In both muscle
diseases, prion, and several proteins characteristic of Alzheimer brain--eg,
beta-amyloid protein and hyperphosphorylated tau (which normally are expressed
mainly in neurons), and apolipoprotein E--are abnormally accumulated in
vacuolated muscle fibers, by unknown mechanisms. We now demonstrate in
both muscle diseases that prion mRNA is strongly expressed in the vacuolated
muscle fibers, which suggests that their accumulated prion protein results,
at least partly, from increased gene expression. This, to our knowledge,
is the first demonstration of abnormally increased prion mRNA in human
disease. Another novel finding is the increased prion mRNA in human muscle
macrophages, and both increased prion protein and prion mRNA in regenerating
muscle fibers. The latter indicates that prion may play a role in human
muscle development. EM - 9503 Molecular genetics of prion diseases in France. French Research Group on Epidemiology of Human Spongiform EncephalopathiesNeurology 1994 Dec;44(12):2347-51 Laplanche JL; Delasnerie-Laupretre N; Brandel JP; Chatelain J; Beaudry P; Alperovitch A; Launay JM Service de Biochimie, Hopital Saint-Louis, Paris, France. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Point Mutation; Prion Diseases [genetics]; Prions [genetics] MN - Adult; Age of Onset; Aged; Codon [genetics]; Creutzfeldt-Jakob Syndrome [physiopathology]; Electroencephalography; France; Genotype; Homozygote; Middle Age; Polymerase Chain Reaction; Polymorphism (Genetics); Prion Diseases [physiopathology]; Reference Values MT - Comparative Study; Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Human prion diseases are characterized by the accumulation
in the brain of an abnormal form of the prion protein. Prion protein polymorphisms
seem to play a key role in the PathoGenesis of these diseases, probably
by enhancing the amyloidogenic properties of the protein. We performed
prion protein gene (PRNP) coding sequence analysis in 57 French subjects
with Creutzfeldt-Jakob disease (CJD) and found a mutation of the PRNP coding
sequence in nine subjects (15.8%); the mutation corresponded with a known
family history of CJD in only three of these subjects. In 41 definite and
probable cases without known PRNP mutations, codon 129 genotyping revealed
an excess of the homozygous 129Met/Met genotype corresponding to a 3.4-fold
increased risk of developing CJD when compared with the two other genotypes.
We also found that the 129Val/Val genotype, which mainly governs susceptibility
to iatrogenic CJD, does not seem to predispose to sporadic CJD. EM - 9503 The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob diseaseThe French Research Group on Epidemiology of Human Spongiform Encephalopathies [see comments] CM - Comment in: Lancet 1995 Jan 7; 345(8941):68; Comment in: Lancet 1995 Jan 7; 345(8941):68-9; Comment in: Lancet 1995 Jan 7; 345(8941):69Lancet 1994 Nov 12;344(8933):1315-8 Amouyel P; Vidal O; Launay JM; Laplanche JL Service d'Epidemiologie, Institut Pasteur de Lille, France. MJ - Alleles; Apolipoproteins E [genetics]; Creutzfeldt-Jakob Syndrome [genetics] MN - Aged; Creutzfeldt-Jakob Syndrome [mortality]; Disease Susceptibility; Genotype; Middle Age; Mutation; Polymorphism, Restriction Fragment Length; Prions [genetics]; Risk Factors; Survival Rate MT - Female; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Creutzfeldt-Jakob disease (CJD) is a rapid progressive
mental and neurological disorder characterised by dementia and is both
infectious and genetic. Pathogenic mutations and a predisposing polymorphism
have been described in the prion protein gene and an abnormal prion product
accumulates in the brain of affected patients. Apolipoprotein E (APOE),
a protein of lipid metabolism, has been detected in some prion protein
deposits. This ApoE exists as three common isoforms, coded by specific
allele (epsilon 2, epsilon 3, epsilon 4). The presence of at least one
epsilon 4 allele was described as a major risk factor for Alzheimer's disease,
another neurodegenerative disorder. From a series of 61 patients with CJD
we found that epsilon 4 allele of the APOE gene was a risk factor for the
disease (p 0.01). This association was observed in both definite and probable
cases, and for patients with and without prion protein gene mutations.
Moreover, in affected subjects, epsilon 2 allele of the APOE gene delayed
occurrence of death (p 0.01) independently of other known mutations influencing
the phenotype of the disease. These effects on neurodegenerative disease
associated with APOE alleles suggest a strong involvement of the APOE locus
in brain metabolism. EM - 9502 |
Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion proteinProc 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 Perceptions of prion diseaseJ 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 syndromeJ 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 Neuropathological phenotype and 'prion protein' genotype correlation in sporadic Creutzfeldt-Jakob diseaseNeuroSci 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 Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion proteinProc 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 Mechanism of scrapie replication[letter; comment] CM - Comment on: Science 1994 Apr 22; 264(5158):530-1Science 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 prionsWest 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 Cell-free formation of protease-resistant prion protein[see comments] CM - Comment in: Nature 1994 Aug 11; 370(6489):419-20Nature 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 NeuroBiology. Catching the culprit prion[news; comment] CM - Comment on: Nature 1994 Aug 11; 370(6489):471-4Nature 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 functionNature 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 Proposed three-dimensional structure for the cellular prion proteinProc 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 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 miceProc 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 Murine scrapie-infected neurons in vivo release excess prion protein into the extracellular spaceNeuroSci 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 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 diseasesProc 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 systemsJ 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 [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):528-9Science 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 Structural clues to prion replication[see comments] CM - Comment in: Science 1994 Sep 9; 265(5178):1510Science 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 diseasesAnn 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 Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphismProc 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 Japanese family with Creutzfeldt-Jakob disease with codon 200 point mutation of the prion protein geneNeurology 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 Prion protein (PrP) is not involved in the PathoGenesis of spongiform encephalopathy in zitter ratsNeuroSci 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 Insights into the role of the immune system in prion diseasesProc 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 diseaseNeuroSci 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 Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteinsProc 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 An Israeli family with Gerstmann-Straussler-Scheinker disease manifesting the codon 102 mutation in the prion protein geneNeurology 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 A new point mutation of the prion protein gene in Creutzfeldt-Jakob diseaseAnn 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 A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesisAnn 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 |
Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodiesProc Natl Acad Sci USA 1993 Nov 15;90(22):10608-12 Prusiner SB; Groth D; Serban A; Koehler R; Foster D; Torchia M; Burton D; Yang SL; De Armond SJ Department of Neurology, University of California, San Francisco 94143. MJ - Prions [genetics]; Scrapie [prevention & control] MN - Antibody Formation; Base Sequence; Brain [metabolism]; DNA Primers [chemistry]; Hamsters; Mice, Knockout; Mice; Molecular Sequence Data; Mutagenesis, Insertional; Nerve Tissue Proteins [genetics] [metabolism]; Prions [Immunology]; Scrapie [genetics] MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE Mice, homozygous for prion protein (PrP) gene ablation
(Prn-p0/0), develop normally and remain well 500 days after inoculation
with murine scrapie prions. In contrast, wild-type mice developed scrapie
165 days after inoculation and most Prn-p0/+ mice, heterozygous for disruption
of the PrP gene, exhibited signs of central nervous system dysfunction
between 400 and 465 days after inoculation. In situ Immunoblots showed
widespread deposition of scrapie PrP (PrPSc) in the brains of both wild-type
Prn-p+/+ and Prn-p0/+ mice, while neither cellular PrP (PrPC) nor PrPSc
was detected in the brains of Prn-p0/0 mice. In contrast to Prn-p+/+ and
Prn-p0/+ mice, Prn-p0/0 mice failed to propagate prion infectivity as measured
by bioassays. Syrian hamster (SHa) PrP transgenes rendered Prn-p0/0 mice
susceptible to prions containing SHaPrPSc. Immunization of Prn-p0/0 mice
with purified, infectious mouse or SHa prions dispersed in Freund's adjuvant
produced antisera that bound mouse, SHa, and human PrP on Western blots.
Presumably, the lack of PrPC expression in Prn-p0/0 mice prevents them
from becoming tolerant to the Immunogen. The resistance of Prn-p0/0 mice
to developing scrapie after inoculation with murine prions supports the
hypothesis that PrPSc is essential for both transmission and PathoGenesis
of the prion diseases. EM - 9403 Genetic and infectious prion diseasesArch Neurol 1993 Nov;50(11):1129-53 Prusiner SB Department of Neurology, University of California, San Francisco. MJ - Prion Diseases [genetics] MN - Animal Diseases [transmission]; Cattle; Creutzfeldt-Jakob Syndrome [etiology]; Encephalopathy, Bovine Spongiform [transmission]; Gerstmann-Straussler Syndrome [etiology] [transmission]; Goat Diseases [genetics]; Goats; Iatrogenic Disease; Kuru [etiology]; Mice; Mutation; Nomenclature; Prion Diseases [pathology] [transmission]; Prions [chemistry] [genetics]; Rats; Rodent Diseases [transmission]; Scrapie [genetics]; Sheep MT - Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE; REVIEW (324 references); REVIEW, TUTORIAL Enriching fractions from Syrian hamster (SHa) brain
for scrapie prion infectivity led to the discovery of the prion protein
(PrP). Prion diseases include scrapie of sheep and bovine spongiform encephalopathy
of cattle as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker
syndrome (GSS) of humans. Transgenic (Tg) mice expressing both SHa and
mouse (Mo) PrP genes were used to probe the molecular basis of the species
barrier and the mechanism of scrapie prion replication. Bioassays of brain
extracts from two scrapie-infected Tg lines showed that the prion inoculum
determines that prions are synthesized de novo, even though the cells express
both PrP genes. Studies with artificial prions produced from chimeric Mo/SHaPrP
transgenes underscore the concept that inoculated prion dictates which
prion will be replicated. Discovery of mutations in the PrP genes of humans
with GSS and familial CJD established that prion diseases are both genetic
and infectious. Transgenic mice expressing high levels of MoPrP-P101L,
corresponding to the GSS point mutation (P102L) in human PrP, spontaneously
develop neurologic dysfunction, spongiform degeneration, and astrocytic
gliosis. Inoculation of brain extracts prepared from these Tg (MoPrP-P101L)
mice produced neurodegeneration in recipient animals after prolonged incubation
times. These results are in accord with those of other studies and argue
that prions are devoid of foreign nucleic acid. Structural investigations
of cellular prion protein (PrPC) and prion protein scrapie (PrPSc) suggest
that the difference may be conformational. Conditions that diminished the
beta-sheet content of PrPSc were the same as those identified previously
that inactivate prion infectivity. Whether prion diversity as reflected
by distinct "strains" producing different patterns of PrPSc accumulation
is due to different conformers of PrPSc remains to be established. Advances
in the purification and characterization of both PrPC and PrPSc seem to
have identified the central event in PrPSc synthesis and prion propagation,
ie, the unfolding of PrPC followed by its refolding into PrPSc. These findings
underscore the fundamental features of prion structure and propagation
that differentiate prions from other transmissible Pathogens. EM - 9401 Accumulation of abnormal prion protein in mice infected with Creutzfeldt-Jakob disease via intraperitoneal route: a sequential studyAm J Pathol 1993 Nov;143(5):1470-9 Muramoto T; Kitamoto T; Tateishi J; Goto I Department of Neuropathology, Faculty of Medicine, Kyushu University 60, Fukuoka, Japan. MJ - Brain Chemistry; Creutzfeldt-Jakob Syndrome; Prions [analysis]; Spinal Cord [chemistry]; Spleen [chemistry] MN - Disease Models, Animal; Injections, Intraperitoneal; Lymph Nodes [chemistry]; Mice; Peyer's Patches [chemistry]; Time Factors MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE We Immunohistochemically studied the location of abnormal
prion protein in the central nervous system and visceral organs at the
clinical and preclinical stages of mice infected with Creutzfeldt-Jakob
disease via intraperitoneal route. Abnormal prion protein was diffusely
distributed in the central nervous system. The sequential study showed
that its stainings were first detected 120 days after inoculation, were
found in all mice after 180 days, and were the most intense and widespread
after 270 days. There was no restricted involvement at the early stages
nor rostrally dominant distribution of the stainings that had been found
in mice infected via intracerebral route. Abnormal prion protein was also
located in the follicular dendritic cells in the spleen, lymph nodes, intestinal
Peyer's patch, and thymus. Its stainings were first detected in the spleen,
lymph nodes, and Peyer's patch 14 or 30 days after inoculation. In the
thymus, however, the stainings were first detected after 210 days in the
germinal centers formed in the medulla. EM - 9402 Scrapie prions alter receptor-mediated calcium responses in cultured cellsNeurology 1993 Nov;43(11):2335-41 Kristensson K; Feuerstein B; Taraboulos A; Hyun WC; Prusiner SB; De Armond SJ Department of Neurology, University of California, San Francisco 94143-0506. MJ - Calcium [metabolism]; Neurons [metabolism] [microbiology]; Prions [metabolism]; Receptors, Cell Surface [physiology] MN - Bradykinin [pharmacology]; Calcium Channels [physiology]; Cell Line; Hamsters; Mesocricetus; Mice; Receptors, Cell Surface [drug effects]; Tumor Cells, Cultured MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE The molecular basis of neurologic dysfunction in prion
diseases is unknown. Spongiform degeneration of neurons is the most characteristic
NeuroPathologic change which raises the possibility of abnormal ion channel
function. Here we examined the regulation of Ca2+ fluxes in two cell lines
chronically infected with scrapie prions, designated ScN2a (scrapie-infected
mouse neuroblatoma) and ScHaB (scrapie-infected hamster brain) cells. In
uninfected HaB cells, bradykinin caused increases in intracellular Ca2+
concentration ([Ca2+]i) by release of Ca2+ from internal stores and influx
of extracellular Ca2+ whereas, in N2a cells, bradykinin increased [Ca2+]i
exclusively from internal stores. Prion infection of both cell lines markedly
reduced or eliminated bradykinin-activated increases in [Ca2+]i, whether
driven by internal or extracellular sources. Stressing the cells with high
extracellular [Ca2+], 8 to 20 mM, led to cytopathologic changes in ScHaB
but not in ScN2a cells. Cytopathology was not preceded by an increase in
[Ca2+]i. These findings indicate that scrapie infection induces abnormalities
in receptor-mediated Ca2+ responses and raise the possibility that nerve
cell dysfunction and degeneration in prion diseases is related to ion channel
aberrations. EM - 9402 London meeting explores the ins and outs of prions[news]Science 1993 Oct 8;262(5131):180-1 Kingman S MJ - Prion Diseases [etiology]; Prions [Pathogenicity] MN - Mice, Knockout; Mice; Prions [chemistry] [genetics] [metabolism]; Scrapie [etiology] MT - Animal; Human PT - MEETING REPORT; NEWS EM - 9401 IS - 0036-8075 LA - English UI - 94023953 RN - 0 (Prions); 0 (PrPSc Proteins) Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): codon 178 mutation and codon 129 polymorphismAm J Hum Genet 1993 Oct;53(4):822-7 Medori R; Tritschler HJ Clinica Neurologica, Universita di Bologna, Italy. MJ - Codon; Mutation; Nerve Tissue Proteins [genetics]; Polymorphism (Genetics); Prion Diseases [genetics]; Prions [genetics] MN - Aged; DNA Mutational Analysis; Heterozygote; Homozygote; Middle Age; Pedigree MT - Female; Human; Male PT - JOURNAL ARTICLE Fatal familial insomnia (FFI) is a disease linked to
a GAC(Asp)-- AAC(Asn) mutation in codon 178 of the prion protein (PrP)
gene. FFI is characterized clinically by untreatable progressive insomnia,
dysautonomia, and motor dysfunctions and is characterized pathologically
by selective thalamic atrophy. We confirmed the 178Asn mutation in the
PrP gene of a third FFI family of French ancestry. Three family members
who are under 40 years of age and who inherited the mutation showed only
reduced perfusion in the basal ganglia on single photon emission computerized
tomography. Some FFI features differ from the clinical and NeuroPathologic
findings associated with 178Asn reported elsewhere. However, additional
intragenic mutations accounting for the phenotypic differences were not
observed in two affected individuals. In other sporadic and familial forms
of Creutzfeldt-Jakob disease and Gerstmann-Straussler syndrome, Met or
Val homozygosity at polymorphic codon 129 is associated with a more severe
phenotype, younger age at onset, and faster progression. In FFI, young
and old individuals at disease onset had 129Met/Val. Moreover, of five
178Asn individuals who are above age-at-onset range and who are well, two
have 129Met and three have 129Met/Val, suggesting that polymorphic site
129 does not modulate FFI phenotypic expression. Genetic Heterogeneity
and environment may play an important role in inter- and intrafamilial
variability of the 178Asn mutation. EM - 9401 Prion diseases. A question of conformation[news]Nature 1993 Sep 30;365(6445):386 Carr K MJ - Prion Diseases; Prions [chemistry] MN - Prion Diseases [etiology]; Protein Conformation MT - Animal; Human PT - NEWS EM - 9401 IS - 0028-0836 LA - English UI - 94019761 RN - 0 (Prions); 0 (PrPSc Proteins) Prion disease scare[news]Nature 1993 Sep 9;365(6442):98 MJ - Attitude to Health; Prion Diseases [psychology] MN - Cattle; Great Britain; Mice; Prion Diseases [transmission] [veterinary] MT - Animal; Human PT - NEWS EM - 9312 IS - 0028-0836 LA - English UI - 93382514 Prion protein is strongly Immunolocalized at the postsynaptic domain of human normal neuromuscular junctionsNeuroSci Lett 1993 Sep 3;159(1-2):111-4 Askanas V; Bilak M; Engel WK; Leclerc A; Tome F Department of Neurology, University of Southern California School of Medicine, Los Angeles 90017-1912. MJ - Neuromuscular Junction [metabolism]; Prions [metabolism]; Synapses [metabolism] MN - Antibodies, Monoclonal [Immunology]; Bungarotoxins [pharmacology]; Cell Membrane [drug effects] [metabolism]; Histocytochemistry; Muscles [metabolism] [pathology]; Prions [Immunology]; Receptors, Cholinergic [drug effects] MT - Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE Using three well-characterized polyclonal and monoclonal
antibodies against prion protein (PrP), we demonstrated a strong concentration
of PrP at human neuromuscular junctions (NMJs). Applying double and triple
fluorescence-labeling, we found that PrP Immunoreactivity exactly co-localized
with alpha-bungarotoxin (alpha-BT) identified acetylcholine receptors,
as well as with the high junctional concentrations of beta-amyloid precursor
protein, beta-amyloid protein, desmin, ubiquitin and dystrophin. Therefore,
PrP was considered to be located on the postsynaptic muscle membrane. At
all NMJs identified by bound alpha-BT, strong PrP Immunoreactivity was
obtained with all PrP antibodies. This appears to be the first demonstration
of PrP concentrated at human NMJs. EM - 9403 A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cellsJ Biol Chem 1993 Jul 25;268(21):15922-8
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