Prions / Search results for T. Copeland :)
Make your own free website on Tripod.com
Literature Search
Especially for Thomas Copeland


Pardon my lack of cropping on the graphics, ha-ha.... This was a quickie. I thought this might add a little color to the abstracts, chah! Please read the tail end of this search for further instructions on remainder of abstracts. Included in this search are the first 100 of 255.


Prions
References (era 1986 - 1996) compiled Fri, May 9, 1997 at 4:00:00 PM



Search Keywords...
  • General search

New diagnostic tests for prion diseases


[editorial; comment] CM - Comment on: N Engl J Med 1996 Sep 26; 335(13):924-30
N Engl J Med 1996 Sep 26;335(13):963-5
Collinge J MJ - Cerebrospinal Fluid Proteins [analysis]; Creutzfeldt-Jakob Syndrome [diagnosis]; Prion Diseases [diagnosis]; Proteins [analysis] MN - Biological Markers [cerebrospinal fluid]; Creutzfeldt-Jakob Syndrome [cerebrospinal fluid]; Prion Diseases [cerebrospinal fluid] [transmission] MT - Human PT - COMMENT; EDITORIAL

EM - 9611
IS - 0028-4793 LA - English
UI - 96365284 RN - 0 (brain 14-3-3 protein); 0 (Biological Markers); 0 (Cerebrospinal Fluid Proteins); 0 (Proteins)


Emerging problems in prion disease

[editorial; comment] CM - Comment on: Can Med Assoc J 1996 Sep 1; 155(5):529-36

Can Med Assoc J 1996 Sep 1;155(5):549-51
Dodelet V; Ricketts M; Cashman NR MJ - Blood Transfusion [adverse effects]; Creutzfeldt-Jakob Syndrome [transmission]; Encephalopathy, Bovine Spongiform [transmission] MN - Cattle; Risk Factors MT - Animal; Human PT - COMMENT; EDITORIAL

The authors comment on the report by Drs. Chris MacKnight and Kenneth Rockwood (see pages 529 to 536 of this issue) on the implications for Canadian physicians of human prion diseases. They argue that there is reason for concern about the possible crossover of bovine spongiform encephalopathy to humans in the form of a variant of Creutzfeldt-Jakob disease (CJD) recently identified in the United Kingdom. A second emerging issue is the potential for the causative agent of CJD to be transmitted through donated blood and tissue. Although the epidemiologic evidence suggests that this risk is remote, current national and international initiatives to increase surveillance for new cases of CJD are timely.

EM - 9612
IS - 0008-4409 LA - English
UI - 96397367


Support for the prion hypothesis for inheritance of a phenotypic trait in yeast

[see comments] CM - Comment in: Science 1996 Aug 2; 273(5275):580
Science 1996 Aug 2;273(5275):622-6
Patino MM; Liu JJ; Glover JR; Lindquist S
Howard Hughes Medical Institute and the Department of Molecular Genetics and Cell Biology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA. MJ - Fungal Proteins [chemistry]; Prions [chemistry]; Protein Conformation; Saccharomyces cerevisiae [chemistry] [genetics] MN - Amino Acid Sequence; Base Sequence; Fungal Proteins [analysis] [genetics] [physiology]; Heat-Shock Proteins [physiology]; Luminescent Proteins [analysis]; Molecular Sequence Data; Phenotype; Prions [genetics]; Recombinant Fusion Proteins [analysis] [chemistry]; Solubility MT - Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

A cytoplasmically inherited genetic element in yeast, [PSI+], was confirmed to be a prionlike aggregate of the cellular protein Sup35 by differential centrifugation analysis and microscopic localization of a Sup35-green fluorescent protein fusion. Aggregation depended on the intracellular concentration and functional state of the chaperone protein Hsp104 in the same manner as did [PSI+] inheritance. The amino-terminal and carboxy-terminal domains of Sup35 contributed to the unusual behavior of [PSI+]. [PSI+] altered the conformational state of newly synthesized prion proteins, inducing them to aggregate as well, thus fulfilling a major tenet of the prion hypothesis.

EM - 9611
IS - 0036-8075 LA - English
UI - 96325424 RN - 0 (Fungal Proteins); 0 (Heat-Shock Proteins); 0 (Luminescent Proteins); 0 (Prions); 0 (Recombinant Fusion Proteins); 133737-87-8 (SUP2 protein); 143012-44-6 (HsP104 protein); 147336-22-9 (green fluorescent protein, Aequorea victoria) ID - GM25874-GM-NIGMS


Yeast prions: DNA-free genetics

[news; comment] CM - Comment on: Science 1996 Aug 2; 273(5275):622-6

Science 1996 Aug 2;273(5275):580
Vogel G MJ - Fungal Proteins [chemistry]; Prions [chemistry]; Protein Conformation; Saccharomyces cerevisiae [chemistry]

MN - Fungal Proteins [analysis] [biosynthesis]; Prions [analysis] [biosynthesis]; Saccharomyces cerevisiae [genetics]; Solubility PT - COMMENT; NEWS EM - 9611
IS - 0036-8075 LA - English
UI - 96345546 RN - 0 (Fungal Proteins); 0 (Prions); 133737-87-8 (SUP2 protein)


Putting prions to the test [news]


Science 1996 Jul 12;273(5272):184-9
Mestel R MJ - PrPC Proteins [chemistry]; Prion Diseases [etiology]; Prions [chemistry] [Pathogenicity] MN - Brain Chemistry; Brain [pathology]; Fungal Proteins [chemistry]; Heat-Shock Proteins [metabolism]; PrPC Proteins [Pathogenicity]; Prion Diseases [pathology] [transmission] [virology]; Protein Folding; Protein Structure, Secondary; Saccharomyces cerevisiae [chemistry]

MT - Animal; Human PT - NEWS EM - 9610
IS - 0036-8075 LA - English
UI - 96298982 RN - 0 (Fungal Proteins); 0 (Heat-Shock Proteins); 0 (Prions); 0 (PrPC Proteins); 143012-44-6 (HsP104 protein)


NMR structure of the mouse prion protein domain PrP (121-321)


Nature 1996 Jul 11;382(6587):180-2
Riek R; Hornemann S; Wider G; Billeter M; Glockshuber R; Wuthrich K
Institut fur Molekularbiologie und Biophysik, Eidgenossische Technische Hochschule-Honggerberg, Zurich, Switzerland. MJ - Peptide Fragments [chemistry]; Prions [chemistry]

MN - Amino Acid Sequence; Mice; Molecular Sequence Data; Nuclear Magnetic Resonance; PrPC Proteins [chemistry]; Protein Conformation; Protein Structure, Secondary MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

The 'protein only' hypothesis states that a modified form of normal prion protein triggers infectious neurodegenerative diseases, such as bovine spongiform encephalopathy (BSE), or Creutzfeldt-Jakob disease (CJD) in humans. Prion proteins are thought to exist in two different conformations: the 'benign' PrPcform, and the infectious 'scrapie form', PrPsc. Knowledge of the three-dimensional structure of PrPc is essential for understanding the transition to PrPsc. The nuclear magnetic resonance (NMR) structure of the autonomously folding PrP domain comprising residues 121-231 (ref. 6) contains a two-stranded antiparallel beta-sheet and three alpha-helices. This domain contains most of the point-mutation sites that have been linked, in human PrP, to the occurrence of familial prion diseases. The NMR structure shows that these mutations occur within, or directly adjacent to, regular secondary structures. The presence of a beta-sheet in PrP(121-231) is in contrast with model predictions of an all-helical structure of PrPc (ref. 8), and may be important for the initiation of the transition from PrPc to PrPsc. EM - 9611

IS - 0028-0836 LA - English
UI - 96317593 RN - 0 (prion protein (121-231); 0 (Peptide Fragments); 0 (Prions); 0 (PrPC Proteins)


Circumventing tolerance to generate autologous monoclonal antibodies to the prion protein


Proc Natl Acad Sci USA 1996 Jul 9;93(14):7279-82
Williamson RA; Peretz D; Smorodinsky N; Bastidas R; Serban H; Mehlhorn I; De Armond SJ; Prusiner SB; Burton DR
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

MJ - Antibodies, Monoclonal [biosynthesis]; Immune Tolerance; Prion Diseases [Immunology]; Prions [Immunology] MN - Antibody Specificity; Base Sequence; DNA Primers; Enzyme-Linked Immunosorbent Assay; Hamsters; Immunoglobulins, Fab [biosynthesis]; Immunoglobulins, Heavy-Chain [biosynthesis]; Mesocricetus; Mice; Molecular Sequence Data; Polymerase Chain Reaction; Prions [analysis]; Recombinant Proteins [biosynthesis] MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

Prion diseases are disorders of protein conformation and do not provoke an immune response. Raising antibodies to the prion protein (PrP) has been difficult due to conservation of the PrP sequence and to inhibitory activity of alpha-PrP antibodies toward lymphocytes. To circumvent these problems, we immunized mice in which the PrP gene was ablated (Prnp 0/0) and retrieved specific monoclonal antibodies (mAbs) through phage display libraries. This approach yielded alpha-PrP mAbs that recognize mouse PrP. Studies with these mAbs suggest that cellular PrP adopts an unusually open structure consistent with the conformational plasticity of this protein. EM - 9610

IS - 0027-8424 LA - English
UI - 96293515 RN - 0 (Antibodies, Monoclonal); 0 (DNA Primers); 0 (Immunoglobulins, Fab); 0 (Immunoglobulins, Heavy-Chain); 0 (Prions); 0 (Recombinant Proteins) ID - AG02132-AG-NIA


Prion phylogeny revisited [letter]


Nature 1996 Jul 4;382(6586):32-3
Goldmann W; Hunter N; Somerville R; Hope J MJ - Prions [classification] MN - Amino Acid Sequence; Cats; Cattle; Codon; Encephalopathy, Bovine Spongiform [transmission]; Mice; Phylogeny; Prions [chemistry] [genetics] [Pathogenicity]; Sheep; Species Specificity

MT - Animal; Human PT - LETTER EM - 9610
IS - 0028-0836 LA - English
UI - 96273017 RN - 0 (Codon); 0 (Prions)


Is hereditary inclusion body myopathy a "familial prion disease"?

[letter]

Ann Neurol 1996 Jul;40(1):128
Cervernakova L; Sivakumar K; Nagle J; Dalakas MC; Goldfarb LG

MJ - Inclusion Bodies; Prion Diseases [genetics] MN - Chromosomes, Human, Pair 20 MT - Human PT - LETTER EM - 9610
IS - 0364-5134 LA - English
UI - 96295949


Preclinical test for prion diseases

[letter]

Nature 1996 Jun 13;381(6583):563
Schreuder BE; van Keulen LJ; Vromans ME; Langeveld JP; Smits MA

MJ - PrPSc Proteins [analysis]; Prion Diseases [diagnosis]; Tonsil [metabolism] MN - Alleles; PrPSc Proteins [genetics]; Scrapie [diagnosis]; Sheep; Time Factors MT - Animal; Human PT - LETTER EM - 9609
IS - 0028-0836 LA - English
UI - 96238855 RN - 0 (PrPSc Proteins)


Prion protein released by platelets

[letter]

Lancet 1996 Jun 8;347(9015):1635-6
Perini F; Frangione B; Prelli F MJ - Blood Platelets [metabolism]; Prions [metabolism] MN - Cells, Cultured; Prion Diseases [metabolism] MT - Human; Support, U.S. Gov't, P.H.S.

PT - LETTER EM - 9610
IS - 0140-6736 LA - English
UI - 96240982 RN - 0 (Prions) ID - AG05891-AG-NIA; AR02594-AR-NIAMS; NS30455-NS-NINDS


Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease


Ann Neurol 1996 Jun;39(6):767-78
Parchi P; Castellani R; Capellari S; Ghetti B; Young K; Chen SG; Farlow M; Dickson DW; Sima AA; Trojanowski JQ; Petersen RB; Gambetti P
Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Phenotype MN - Adult; Aged; Astrocytes [ultrastructure]; Blotting, Western; Brain [drug effects] [physiopathology] [ultrastructure]; Codon [genetics]; Creutzfeldt-Jakob Syndrome [drug therapy] [physiopathology]; Genotype; Glycosylation; Homozygote; Immunohistochemistry; Methionine [genetics]; Middle Age; Prions [genetics] [ultrastructure]; Serine Proteinases [pharmacology] [therapeutic use]; Tissue Culture

MT - Female; Human; Male; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and Immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.

EM - 9609
IS - 0364-5134 LA - English
UI - 96256496 RN - EC 3.4.21 (Serine Proteinases); EC 3.4.21.64 (endopeptidase K); 0 (Codon); 0 (Prions); 7005-18-7 (Methionine) ID - AG08992-AG-NIA; AG10133-AG-NIA; AG08155-AG-NIA; +


Two mutant prion proteins expressed in cultured cells acquire biochemical properties reminiscent of the scrapie isoform


Proc Natl Acad Sci USA 1996 May 28;93(11):5610-4
Lehmann S; Harris DA
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. MJ - Prions [biosynthesis]; Scrapie [genetics] MN - Amino Acid Sequence; CHO Cells; Creutzfeldt-Jakob Syndrome [genetics] [virology]; Hamsters; Kinetics; Mice; Molecular Sequence Data; Point Mutation; Prions [chemistry] [isolation & purification]; Recombinant Proteins [biosynthesis] [chemistry] [isolation & purification]; Sequence Tagged Sites; Transfection

MT - Animal; Comparative Study; Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

Prion diseases are a group of fatal neurodegenerative disorders that are unique in being infectious, genetic, and sporadic in origin. Infectious cases are caused by prions, which are composed primarily of PrPSc, a posttranslationally modified isoform of the normal cellular prion protein PrPC. Inherited cases are linked to insertional or point mutations in the host gene encoding PrPC. To investigate the molecular mechanisms underlying inherited prion diseases, we have constructed stably transfected Chinese hamster ovary cells that express mouse PrPs homologous to two human PrPs associated with familial Creutzfeldt-Jakob disease. One mouse PrP molecule carries a Glu-- Lys substitution at codon 199, and the other carries an insertion of six additional octapeptide repeats between codons 51 and 90. We find that both of these mutant PrPs display several biochemical hallmarks of PrPSc when synthesized in cell culture. Unlike wild-type PrP, the mutant proteins are detergent insoluble and are relatively resistant to digestion by proteinase K, yielding an N-terminally truncated core fragment of 27-30 kDa. Pulse-chase labeling experiments demonstrate that these properties are acquired posttranslationally, and are accompanied by increased metabolic stability of the protein. Our results provide the first evidence that a molecule with properties reminiscent of PrPSc can be generated de novo in cultured cells.

EM - 9609
IS - 0027-8424 LA - English
UI - 96224334 RN - 0 (Prions); 0 (Recombinant Proteins) 


Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein


J 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+ currents


NeuroSci 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 Scrapie

Van Keulen LJ; Schreuder BE; Meloen RH; Mooij-Harkes G; Vromans ME; Langeveld JP
J Clin Microbiol 1996 May;34(5):1228-31
Department of Pathobiology and Epidemiology,
Institute for Animal Science and Health,
Lelystad, The Netherlands
UI # 96284431
Abstract

The Scrapie-associated form of the Prion Protein (PrPSc) accumulates in the Brain and Lymphoid tissues of sheep with Scrapie.

In order to assess whether detecting PrPSc in Lymphoid tissue could be used as a diagnostic test for scrapie, we studied the localization and distribution of PrPSc in various Lymphoid tissues collected at necropsy from 55 sheep with clinical Scrapie.

Samples collected from the Spleen, Palatine Tonsil, Ileum, and five different Lymph Nodes were ImmunoHistoChemically stained for PrPSc.

PrPSc was found to be deposited in a reticular pattern in the center of both primary and secondary Lymphoid Follicles. In addition, granules of PrPSc were seen in the CytoPlasm in Macrophages associated with the Lymphoid Follicles.

In 54 (98%) of the 55 Scrapie-affected sheep, PrPSc was detected in the Spleen, retropharyngeal Lymph Node, Mesenteric Lymph Node, and the Palatine Tonsil.

However, only in the Palatine Tonsils was PrPSc present in a consistently high percentage of the Lymphoid Follicles.

PrP was not detected in any of the Lymphoid tissues of 12 sheep that had no NeuroHistoPathological signs of a Scrapie infection.

We conclude that the Tonsils are the best-suited Lymphoid tissue to be biopsied for the detection of PrPSc in the diagnosis of clinical Scrapie in living sheep.

EM - 9612
IS - 0095-1137 LA - English
UI - 96284431 RN - 0 (Antibodies); 0 (PrPSc Proteins)


Phylogenesis of prion protein

[letter]
Nature 1996 Apr 25;380(6576):675
Krakauer DC; Pagel M; Southwood TR; Zanotto PM
Department of Zoology, University of Oxford, UK. MJ - Mammals [classification]; Phylogeny; Prions [genetics] MN - Mammals [genetics]; Mutation; Prion Diseases [genetics]; Prions [classification] MT - Animal; Human PT - LETTER EM - 9608
IS - 0028-0836 LA - English
UI - 96202723 RN - 0 (Prions) 

Altered circadian activity rhythms and sleep in mice devoid of prion protein


Nature 1996 Apr 18;380(6575):639-42
Tobler I; Gaus SE; Deboer T; Achermann P; Fischer M; Rulicke T; Moser M; Oesch B; McBride PA; Manson JC
Institute of Pharmacology, University of Zurich, Switzerland. MJ - Circadian Rhythm [physiology]; Prions; Sleep [physiology] MN - Circadian Rhythm [genetics]; Mice, Inbred C57BL; Mice; Motor Activity; Mutation; Prion Diseases [genetics] [physiopathology]; Prions [genetics]; Sleep [genetics] MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

There is a wealth of data supporting a central role for the prion protein (PrP) in the neurodegenerative prion diseases of both humans and other species, yet the normal function of PrP, which is expressed at the cell surface of neurons and glial cells, is unknown. It has been speculated that NeuroPathology may be due to loss of normal function of PrP. Here we show that in mice devoid of PrP there is an alteration in both circadian activity rhythms and patterns. To our knowledge, this is the first null mutation that has been shown to affect sleep regulation and our results indicate that at least one of the inherited prion diseases, fatal familial insomnia, where there is a profound alteration in sleep and the daily rhythms of many hormones, may be related to the normal function of the prion protein. EM - 9607
IS - 0028-0836 LA - English
UI - 96186816 RN - 0 (Prions) 


Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene


Nature 1996 Apr 11;380(6574):528-31
Sakaguchi S; Katamine S; Nishida N; Moriuchi R; Shigematsu K; Sugimoto T; Nakatani A; Kataoka Y; Houtani T; Shirabe S; Okada H; Hasegawa S; Miyamoto T; Noda T
Department of Bacteriology, Nagasaki University School of Medicine, Nagasaki, Japan. MJ - Cell Death; Homozygote; Prions [genetics]; Purkinje Cells [pathology] MN - Ataxia [genetics]; Brain [pathology]; Drug Resistance [genetics]; Glutamate Decarboxylase [metabolism]; Heterozygote; Mice; Mutagenesis; Prion Diseases [genetics] MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

Prion protein (PrP) is a glycoprotein constitutively expressed on the neuronal cell surface. A protease-resistant isoform of prion protein is implicated in the PathoGenesis of a series of transmissible spongiform encephalopathies. We have developed a line of mice homozygous for a disrupted PrP gene in which the whole PrP-coding sequence is replaced by a drug-resistant gene. In keeping with previous results, we find that homozygous loss of the PrP gene has no deleterious effect on the development of these mice and renders them resistant to prion. The PrP-null mice grew normally after birth, but at about 70 weeks of age all began to show progressive symptoms of ataxia. Impaired motor coordination in these ataxic mice was evident in a rotorod test. Pathological examination revealed an extensive loss of Purkinje cells in the vast majority of cerebellar folia, suggesting that PrP plays a role in the long-term survival of Purkinje neurons. EM - 9607
IS - 0028-0836 LA - English
UI - 96195059 RN - EC 4.1.1.15 (Glutamate Decarboxylase); 0 (Prions) 


Prions and hospital infections

[letter]
Lancet 1996 Apr 6;347(9006):966-7
van Asten JA; Geertsma RE; Dorpema JW MJ - Cross Infection [prevention & control]; Prion Diseases [prevention & control]; Prions; Sterilization [methods] MT - Human PT - LETTER EM - 9606
IS - 0140-6736 LA - English
UI - 96178708 RN - 0 (Prions) 

A new variant of prion disease

[comment] CM - Comment on: Lancet 1996 Apr 6; 347(9006):921-5; Comment on: Lancet 1996 Apr 6; 347(9006):945-8
Lancet 1996 Apr 6;347(9006):916-7
Collinge J; Rossor M
Department of Biochemistry and Molecular Genetics, Imperial College School of Medicine at St. Mary's, London, UK. MJ - Creutzfeldt-Jakob Syndrome; Prion Diseases MN - Adolescence; Adult; Cattle; Creutzfeldt-Jakob Syndrome [genetics] [pathology] [physiopathology]; Encephalopathy, Bovine Spongiform [pathology] [transmission]; Mutation; PrPSc Proteins [genetics]; Prion Diseases [genetics] [pathology] [physiopathology] MT - Animal; Human PT - COMMENT; JOURNAL ARTICLE EM - 9606
IS - 0140-6736 LA - English
UI - 96178684 RN - 0 (PrPSc Proteins) 

Role of microglia and host prion protein in neurotoxicity of a prion protein fragment


Nature 1996 Mar 28;380(6572):345-7
Brown DR; Schmidt B; Kretzschmar HA
Institut fur Neuropathologie, Universitat Gottingen, Germany. MJ - Cerebellum [drug effects]; Microglia [physiology]; Neurotoxins [toxicity]; Peptide Fragments [toxicity]; Prions [toxicity] MN - Amino Acid Sequence; Cell Survival [drug effects]; Cells, Cultured; Cerebellum [pathology]; Coculture; Leucine [analogs & derivatives] [pharmacology]; Mice, Inbred C57BL; Mice; Microglia [drug effects]; Molecular Sequence Data; Oxidative Stress; PrPC Proteins [biosynthesis] MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

The prion protein PrPc is a glycoprotein of unknown function normally found in neurons and glia. It is involved in diseases such as bovine spongiform encephalopathy (BSE), scrapie and Creutzfeldt-Jakob disease. PrPSc, an altered isoform of PrPC that is associated with disease, shows greater protease resistance and is part of the infectious agent, the prion. Prion diseases are characterized by neuronal degeneration, gliosis and accumulation of PrPSc. Mice devoid of PrPC are resistant to scrapie. A fragment of human PrP consisting of amino acids 106-126 that forms fibrils in vitro is toxic to cultured neurons. Here we show that this toxic effect requires the presence of microglia which respond to PrP106-126 by increasing their oxygen radical production. The combined direct and microglia-mediated effects of PrP106-126 are toxic to normal neurons but are insufficient to destroy neurons from mice not expressing PrPC. EM - 9606
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) 


Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus


Proc Natl Acad Sci USA 1996 Mar 19;93(6):2403-7
Lledo PM; Tremblay P; De Armond SJ; Prusiner SB; Nicoll RA
Department of Cellular and Molecular Pharmacology and Physiology, University of California, San Francisco 94143, USA. MJ - Hippocampus [physiology]; Prions [pharmacology] MN - Action Potentials; Long-Term Potentiation [physiology]; Mice, Knockout; Mice; Synaptic Transmission MT - Animal; Female; In Vitro; Male; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus. EM - 9609
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 gene


Neurology 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
IS - 0028-3878 LA - English
UI - 96173688 RN - 0 (DNA Insertion Elements); 0 (Molecular Probes); 0 (Prions); 9007-49-2 (DNA) 


Normal host prion protein necessary for scrapie-induced neurotoxicity


Nature 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
IS - 0028-0836 LA - English
UI - 96149246 RN - 0 (PrPC Proteins); 0 (PrPSc Proteins) 


Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP


Proc 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
IS - 0027-8424 LA - English
UI - 96149376 RN - 0 (Amyloid); 0 (Prions) ID - NS29822-NS-NINDS; P30 AG10133-AG-NIA 


Mutant and infectious prion proteins display common biochemical properties in cultured cells


J 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
IS - 0021-9258 LA - English
UI - 96139500 RN - EC 3.1.4.3 (Phospholipase C); EC 3.4.- (Peptide Peptidohydrolases); 0 (Detergents); 0 (Prions); 0 (PrPSc Proteins); 0 (Recombinant Proteins) 


Unaltered susceptibility to BSE in transgenic mice expressing human prion protein

[see comments] CM - Comment in: Nature 1995 Dec 21-28; 378(6559):759
Nature 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
IS - 0028-0836 LA - English
UI - 96112013 RN - 0 (Prions); 0 (PrPSc Proteins); 0 (Recombinant Proteins) 


Hypokinesia and presenile dementia in a Dutch family with a novel insertion in the prion protein gene


Brain 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
IS - 0006-8950 LA - English
UI - 96146585 RN - 0 (DNA Insertion Elements); 0 (Prions) 


Prion disease (PrP-A117V) presenting with ataxia instead of dementia


Neurology 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
IS - 0028-3878 LA - English
UI - 96063532 RN - 9007-49-2 (DNA) ID - NS14069-NS-NINDS; AG08967-AG-NIA; AG02132-AG-NIA; + 


Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells


Science 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
IS - 0036-8075 LA - English
UI - 96008581 RN - EC 3.4.21 (Serine Proteinases); EC 3.4.21.- (Tritirachium alkaline proteinase); 0 (Fungal Proteins); 0 (Plasmids); 0 (Prions); 134773-68-5 (URE2 protein); 7727-37-9 (Nitrogen) 


Prion protein isoforms, a convergence of biological and structural investigations


J 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 diseases


J 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
IS - 0021-9258 LA - English
UI - 95370239 RN - 0 (Peptide Fragments); 0 (Prions) ID - AG08155-AG-NIA; AG08992-AG-NIA 


The abnormal isoform of the prion protein accumulates in late-endosome-like organelles in scrapie-infected mouse brain


J 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
IS - 0022-3417 LA - English
UI - 96030727 RN - 0 (Prions) 


Regional distribution of protease-resistant prion protein in fatal familial insomnia


Ann 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
IS - 0364-5134 LA - English
UI - 95336147 RN - EC 3.4.- (Peptide Peptidohydrolases); 0 (Glial Fibrillary Acidic Protein); 0 (Prions); 0 (PrPC Proteins) ID - AG08012-AG-NIA; AG08155-AG-NIA; AG08992-AG-NIA 


Non-genetic propagation of strain-specific properties of scrapie prion protein

[see comments] CM - Comment in: Nature 1995 Jun 22; 375(6533):628-9
Nature 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
IS - 0028-0836 LA - English
UI - 95312110 RN - EC 3.4.21 (Serine Proteinases); EC 3.4.21.- (Tritirachium alkaline proteinase); 0 (Guanidines); 0 (Prions); 0 (PrPC Proteins); 0 (PrPSc Proteins); 113-00-8 (guanidine); 7773-52-6 (Cetylpyridinium) 


Prion diseases. Yielding under the strain

[news; comment] CM - Comment on: Nature 1995 Jun 22; 375(6533):698-700
Nature 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
IS - 0036-8075 LA - English
UI - 95273963 RN - 0 (Fungal Proteins); 0 (Heat-Shock Proteins); 0 (Prions); 143012-44-6 (HsP104 protein) 


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 barrier


Proc 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
IS - 0027-8424 LA - English
UI - 95249584 RN - EC 3.4.- (Peptide Peptidohydrolases); 0 (Prions); 11089-65-9 (Tunicamycin) 


Etiology and PathoGenesis of prion diseases


Am 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 cells


Proc 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
IS - 0027-8424 LA - English
UI - 95224056 RN - 0 (DNA-Binding Proteins); 0 (Heat-Shock Proteins); 0 (Prions); 0 (Transcription Factors); 136111-36-9 (heat shock factor, human) 


Allelic variations in apolipoprotein E and prion protein genotype related to plaque formation and age of onset in sporadic Creutzfeldt-Jakob disease


NeuroSci 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
IS - 0304-3940 LA - English
UI - 95303365 RN - 0 (Apolipoproteins E); 0 (Prions) 


Developmental expression of the prion protein gene in glial cells


Neuron 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
IS - 0896-6273 LA - English
UI - 95209857 RN - 0 (Prions); 0 (RNA Probes); 0 (RNA, Messenger) 


Prion protein accumulation in the spinal cords of patients wih sporadic and growth hormone associated Creutzfeldt-Jakob disease


NeuroSci 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
IS - 0304-3940 LA - English
UI - 95265264 RN - 0 (Antibodies); 0 (Prions); 9002-72-6 (Somatotropin) 


Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions


Neuron 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
IS - 0896-6273 LA - English
UI - 95127230 RN - EC 3.2.1.23 (beta-Galactosidase); 0 (Glial Fibrillary Acidic Protein); 0 (Prions); 0 (RNA, Messenger); 0 (Vimentin) 


The prion diseases


Sci 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 gene


J 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
IS - 0022-3050 LA - English
UI - 95123377 RN - 0 (DNA Insertion Elements); 0 (DNA Primers); 0 (Prions); 0 (Proteins) 


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):1261-4
Am 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
IS - 0002-9440 LA - English
UI - 95084997 RN - 0 (Prions); 0 (RNA, Messenger) 


Molecular genetics of prion diseases in France. French Research Group on Epidemiology of Human Spongiform Encephalopathies


Neurology 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
IS - 0028-3878 LA - English
UI - 95083118 RN - 0 (Codon); 0 (Prions) 


The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease

The 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):69
Lancet 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
IS - 0140-6736 LA - English
UI - 95057605 RN - 0 (Apolipoproteins E); 0 (Prions)
 


Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein


Proc Natl Acad Sci USA 1994 Oct 11;91(21):9936-40
Telling GC; Scott M; Hsiao KK; Foster D; Yang SL; Torchia M; Sidle KC; Collinge J; De Armond SJ; Prusiner SB
Department of Neurology, University of California, San Francisco 94143. MJ - Brain [pathology]; Chimeric Proteins [biosynthesis]; Creutzfeldt-Jakob Syndrome [genetics] [physiopathology]; Prions [biosynthesis] MN - Astrocytes [metabolism] [pathology]; Brain [metabolism]; Chimeric Proteins [analysis]; Creutzfeldt-Jakob Syndrome [pathology]; Mice, Transgenic; Mice; Open Reading Frames; Polymerase Chain Reaction [methods]; Prions [analysis] [genetics]; Restriction Mapping; Time Factors MT - Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

Transgenic (Tg) mice were constructed that express a chimeric prion protein (PrP) in which a segment of mouse (Mo) PrP was replaced with the corresponding human (Hu) PrP sequence. The chimeric PrP, designated MHu2MPrP, differs from MoPrP by 9 amino acids between residues 96 and 167. All of the Tg(MHu2M) mice developed neurologic disease approximately 200 days after inoculation with brain homogenates from three patients dying of Creutzfeldt-Jakob disease (CJD). Inoculation of Tg(MHu2M) mice with CJD prions produced MHu2MPrPSc (where PrPSc is the scrapie isoform of PrP); inoculation with Mo prions produced Mo-PrPSc. The patterns of MHu2MPrPSc and MoPrPSc accumulation in the brains of Tg(MHu2M) mice were different. About 10% of Tg(HuPrP) mice expressing HuPrP and non-Tg mice developed neurologic disease 500 days after inoculation with CJD prions. The different susceptibilities of Tg(HuPrP) and Tg(MHu2M) mice to Hu prions indicate that additional species-specific factors are involved in prion replication. Diagnosis, prevention, and treatment of Hu prion diseases should be facilitated by Tg(MHu2M) mice. EM - 9501
IS - 0027-8424 LA - English
UI - 95024076 RN - 0 (Chimeric Proteins); 0 (Prions) 


Perceptions of prion disease


J Clin Pathol 1994 Oct;47(10):876-9
Ridley RM MJ - Prion Diseases [diagnosis] MN - Adolescence; Adult; Aged; Brain [pathology]; Child, Preschool; Child; Infant; Middle Age; Mutation; Nerve Tissue Proteins [genetics]; Pedigree; Prion Diseases [genetics]; Prions [genetics] MT - Female; Human; Male PT - JOURNAL ARTICLE; REVIEW (15 references); REVIEW, TUTORIAL EM - 9502
IS - 0021-9746 LA - English
UI - 95051609 RN - 0 (Nerve Tissue Proteins); 0 (Prions) 

Absence of disease related prion protein in neurodegenerative disorders presenting with Parkinson's syndrome


J Neurol NeuroSurg Psychiatry 1994 Oct;57(10):1249-51
Jendroska K; Hoffmann O; Schelosky L; Lees AJ; Poewe W; Daniel SE
Department of Neurology, Universitatsklinikum Rudolf Virchow, Berlin, Germany. MJ - Brain [pathology]; Parkinson Disease [pathology]; Prions [analysis] MN - Brain Diseases [pathology]; Creutzfeldt-Jakob Syndrome [pathology]; Dementia, Presenile [pathology]; Immunohistochemistry; Nerve Degeneration; Supranuclear Palsy, Progressive [pathology] MT - Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

Movement disorders presenting with parkinsonism may share histopathological features with Creutzfeldt-Jakob disease, a spongiform encephalopathy caused by the accumulation of pathological prion protein in brain. To investigate a possible aetiological link between these conditions and Creutzfeldt-Jakob disease, histoblot Immunostaining for pathological prion protein was carried out in 90 cases including idiopathic Parkinson's disease, multiple system atrophy, diffuse Lewy body disease, Steele-Richardson-Olszewski syndrome, corticobasal degeneration, and Pick's disease. Pathological prion protein was identified in four controls with Creutzfeldt-Jakob disease but not in any of the other diseases examined. The findings suggest that an aetiological role for prions in these movement disorders is unlikely. Histoblotting provides a useful method for screening large areas of tissue for the presence of pathological prion protein and may be helpful in the differential diagnosis of difficult cases. EM - 9501
IS - 0022-3050 LA - English
UI - 95016781 RN - 0 (Prions) 


Neuropathological phenotype and 'prion protein' genotype correlation in sporadic Creutzfeldt-Jakob disease


NeuroSci Lett 1994 Sep 26;179(1-2):50-2
de Silva R; Ironside JW; McCardle L; Esmonde T; Bell J; Will R; Windl O; Dempster M; Estibeiro P; Lathe R
National Creutzfeldt-Jakob disease surveillance unit, Western General Hospital, Edinburgh, UK. MJ - Creutzfeldt-Jakob Syndrome [genetics] [pathology]; Prions [biosynthesis] MN - Aged, 80 and over; Aged; Amyloidosis [pathology]; Amyloid [genetics] [metabolism]; Creutzfeldt-Jakob Syndrome [metabolism]; DNA [analysis]; Genotype; Methionine [metabolism]; Middle Age; Open Reading Frames; Phenotype; Polymerase Chain Reaction; Polymorphism (Genetics); Prions [genetics]; Valine [metabolism] MT - Human PT - JOURNAL ARTICLE

A systematic study of 'prion protein' genotype in cases of sporadic Creutzfeldt-Jakob disease showing amyloid plaques staining with anti-prion protein antibody has been performed. This revealed a relative excess of cases with valine at position 129 of the gene's open reading frame. The observation emphasises the importance of this site of common polymorphism in influencing the NeuroPathological phenotype in human spongiform encephalopathy. EM - 9505
IS - 0304-3940 LA - English
UI - 95148156 RN - 0 (Amyloid); 0 (Prions); 7004-03-7 (Valine); 7005-18-7 (Methionine); 9007-49-2 (DNA) 


Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein


Proc Natl Acad Sci USA 1994 Sep 13;91(19):9126-30
Hsiao KK; Groth D; Scott M; Yang SL; Serban H; Rapp D; Foster D; Torchia M; Dearmond SJ; Prusiner SB
Department of Neurology, University of California, San Francisco 94143. MJ - Gerstmann-Straussler Syndrome [genetics]; Prions [genetics]; Scrapie [genetics] MN - Hamsters; Mesocricetus; Mice, Transgenic; Mice; Mutation; Prions [metabolism]; Scrapie [pathology] [transmission] MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

Two lines of transgenic (Tg) mice expressing high (H) levels of the mutant P101L prion protein (PrP) developed a neurologic illness and central nervous system pathology indistinguishable from experimental murine scrapie; these mice were designated Tg(MoPrP-P101L)H. Brain homogenates from Tg(MoPrP-P101L)H mice were inoculated intracerebrally into CD-1 Swiss mice, Syrian hamsters, and Tg196 mice, Tg mice expressing the MoPrP-P101L transgene at low levels. None of the CD-1 mice developed central nervous system dysfunction, whereas approximately 10% of hamsters and approximately 40% of the Tg196 mice manifested neurologic signs between 117 and 639 days after inoculation. Serial transmission of neurodegeneration in Tg196 mice and Syrian hamsters was initiated with brain extracts, producing incubation times of approximately 400 and approximately 75 days, respectively. Although the Tg(MoPrP-P101L)H mice appear to accumulate only low levels of infections prions in their brains, the serial transmission of disease to inoculated recipients argues that prion formation occurs de novo in the brains of these uninoculated animals. These Tg mouse studies, taken together with similar findings in humans dying of inherited prion diseases, provide additional evidence that prions lack a foreign nucleic acid. EM - 9412
IS - 0027-8424 LA - English
UI - 94377505 RN - 0 (Prions); 0 (PrPSc Proteins) 


Mechanism of scrapie replication

[letter; comment] CM - Comment on: Science 1994 Apr 22; 264(5158):530-1
Science 1994 Sep 9;265(5178):1510
Lansbury PT MJ - Prions [chemistry] MN - Polymers; Prions [biosynthesis]; Protein Folding PT - COMMENT; LETTER EM - 9412
IS - 0036-8075 LA - English
UI - 94360231 RN - 0 (Polymers); 0 (Prions) 

Neurodegeneration in humans caused by prions


West J Med 1994 Sep;161(3):264-72
Prusiner SB
Department of Neurology, University of California, San Francisco, School of Medicine 94143-0518. MJ - Nerve Degeneration [physiology]; Prion Diseases [physiopathology] MN - Prion Diseases [diagnosis] [genetics] [metabolism] [transmission]; Prions [genetics] [metabolism] MT - Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE; REVIEW (114 references); REVIEW, TUTORIAL

Prion diseases include kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia of humans as well as scrapie and bovine spongiform encephalopathy of animals. For many years, the prion diseases were thought to be caused by viruses despite evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve aberrant metabolism of the prion protein. In many cases, the cellular prion protein is converted into the scrapie variant by a process after translation that involves a conformational change. Often the human prion diseases are transmissible experimentally to animals, and all of the inherited prion diseases segregate with prion protein gene mutations. EM - 9502
IS - 0093-0415 LA - English
UI - 95066029 RN - 0 (Prions) ID - NS14069-NS-NINDS; AG08967-AG-NIA; AG02132-AG-NIA; + 


Cell-free formation of protease-resistant prion protein

[see comments] CM - Comment in: Nature 1994 Aug 11; 370(6489):419-20
Nature 1994 Aug 11;370(6489):471-4
Kocisko DA; Come JH; Priola SA; Chesebro B; Raymond GJ; Lansbury PT; Caughey B
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139. MJ - Peptide Peptidohydrolases [metabolism]; Prions [metabolism] MN - Alzheimer's Disease [metabolism]; Cell-Free System; Hamsters; Mice; Protein Denaturation; Tumor Cells, Cultured MT - Animal; Human; Support, U.S. Gov't, Non-P.H.S. PT - JOURNAL ARTICLE

The infectious agent (or 'prion') of the transmissible spongiform encephalopathies (TSEs) such as scrapie resembles a virus in that it replicates in vivo and has distinct strains, but it was postulated long ago to contain only protein. More recently, PrPSc, a Pathogenic, scrapie-associated form of the host-encoded prion protein (PrP), was identified as a possible primary TSE agent protein. PrPSc is defined biochemically by its insolubility and resistance to proteases and is derived post-translationally from normal, protease-sensitive PrP (PrPc). The conversion seems to involve conformational change rather than covalent modification. However, the conversion mechanism and the relationship of PrPSc formation to TSE agent replication remain unclear. Here we report the conversion of PrPc to protease-resistant forms similar to PrPSc in a cell-free system composed of substantially purified constituents. This conversion was selective and required the presence of preexisting PrPSc, providing direct evidence that PrPSc derives from specific PrPc-PrPSc interactions. EM - 9411
IS - 0028-0836 LA - English
UI - 94322940 RN - EC 3.4.- (Peptide Peptidohydrolases); 0 (Prions); 0 (PrPSc Proteins) 


NeuroBiology. Catching the culprit prion

[news; comment] CM - Comment on: Nature 1994 Aug 11; 370(6489):471-4
Nature 1994 Aug 11;370(6489):419-20
Beyreuther K; Masters CL MJ - Peptide Peptidohydrolases [metabolism]; Prions [metabolism] MN - Cell-Free System; Prion Diseases [transmission]; Prions [chemistry]; Protein Conformation MT - Animal; Human PT - COMMENT; NEWS EM - 9411
IS - 0028-0836 LA - English
UI - 94322932 RN - EC 3.4.- (Peptide Peptidohydrolases); 0 (Prions) 

Genetics. Psi no more for yeast prions

[news]
Nature 1994 Aug 4;370(6488):327-8
Tuite MF MJ - Prions [genetics]; Saccharomyces cerevisiae [genetics] MN - Amino Acid Sequence; Molecular Sequence Data; Phenotype MT - Human PT - NEWS EM - 9411
IS - 0028-0836 LA - English
UI - 94322902 RN - 0 (Prions) 

Prion protein is necessary for normal synaptic function


Nature 1994 Jul 28;370(6487):295-7
Collinge J; Whittington MA; Sidle KC; Smith CJ; Palmer MS; Clarke AR; Jefferys JG
Department of Biochemistry and Molecular Genetics, St Mary's Hospital Medical School, Imperial College, London, UK. MJ - Prions; Synapses [physiology] MN - Action Potentials; GABA [metabolism]; Hippocampus [physiology]; Mice, Inbred C57BL; Mice; Nerve Degeneration; Prion Diseases [physiopathology]; Pyramidal Cells [physiology] MT - Animal; In Vitro; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

The prion diseases are neurodegenerative conditions, transmissible by inoculation, and in some cases inherited as an autosomal dominant disorder. They include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. The prion consists principally of a post-translationally modified form of a host-encoded glycoprotein (PrPC), designated PrPSc (ref. 1); the normal cellular function of PrPC is, however, unknown. Although PrP is highly conserved among mammals and widely expressed in early embryogenesis, mice homozygous for disrupted PrP genes appear developmentally and behaviorally normal. PrP is a protein anchored to the neuronal surface by glycosylphosphatidylinositol, suggesting a role in cell signalling or adhesion. Here we report that hippocampal slices from PrP null mice have weakened GABAA (gamma-aminobutyric acid type A) receptor-mediated fast inhibition and impaired long-term potentiation. This impaired synaptic inhibition may be involved in the epileptiform activity seen in Creutzfeldt-Jakob disease and we argue that loss of function of PrPC may contribute to the early synaptic loss and neuronal degeneration seen in these diseases. EM - 9410
IS - 0028-0836 LA - English
UI - 94309735 RN - 0 (Prions); 56-12-2 (GABA) 


Proposed three-dimensional structure for the cellular prion protein


Proc Natl Acad Sci USA 1994 Jul 19;91(15):7139-43
Huang Z; Gabriel JM; Baldwin MA; Fletterick RJ; Prusiner SB; Cohen FE
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143. MJ - Prions [chemistry] MN - Amino Acid Sequence; Circular Dichroism; Crystallography, X-Ray; Molecular Sequence Data; Nuclear Magnetic Resonance; Protein Structure, Secondary; Protein Structure, Tertiary; Spectrophotometry, Infrared MT - Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

Prion diseases are a group of neurodegenerative disorders in humans and animals that seem to result from a conformational change in the prion protein (PrP). Utilizing data obtained by circular dichroism and infrared spectroscopy, computational studies predicted the three-dimensional structure of the cellular form of PrP (PrPc). A heuristic approach consisting of the prediction of secondary structures and of an evaluation of the packing of secondary elements was used to search for plausible tertiary structures. After a series of experimental and theoretical constraints were applied, four structural models of four-helix bundles emerged. A group of amino acids within the four predicted helices were identified as important for tertiary interactions between helices. These amino acids could be essential for maintaining a stable tertiary structure of PrPc. Among four plausible structural models for PrPc, the X-bundle model seemed to correlate best with 5 of 11 known point mutations that segregate with the inherited prion diseases. These 5 mutations cluster around a central hydrophobic core in the X-bundle structure. Furthermore, these mutations occur at or near those amino acids which are predicted to be important for helix-helix interactions. The three-dimensional structure of PrPc proposed here may not only provide a basis for rationalizing mutations of the PrP gene in the inherited prion diseases but also guide design of genetically engineered PrP molecules for further experimental studies. EM - 9410
IS - 0027-8424 LA - English
UI - 94316653 RN - 0 (Prions); 0 (PrPSc Proteins) 


Prions and public health

[editorial]
Nature 1994 Jul 7;370(6484):2 MJ - Creutzfeldt-Jakob Syndrome [transmission]; Encephalopathy, Bovine Spongiform [transmission]; Meat; Prions; Public Health MN - Cattle; Germany; Great Britain MT - Animal; Human PT - EDITORIAL EM - 9409
IS - 0028-0836 LA - English
UI - 94286000 RN - 0 (Prions) 

Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice


Proc Natl Acad Sci USA 1994 Jun 7;91(12):5690-4
Carlson GA; Ebeling C; Yang SL; Telling G; Torchia M; Groth D; Westaway D; De Armond SJ; Prusiner SB
McLaughlin Research Institute, Great Falls, MT 59405. MJ - Prions [genetics] [Pathogenicity]; Scrapie [genetics] MN - Alleles; Brain [metabolism]; Mice, Inbred Strains; Mice, Transgenic; Mice; Prions [metabolism] MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

Different prion isolates, often referred to as "strains," present an enigma because considerable evidence argues that prions are devoid of nucleic acid. To investigate prion diversity, we inoculated three "strains" of prions into congenic and transgenic mice harboring variable numbers of two different alleles, designated a and b, of the prion protein (PrP) structural gene, Prn-p. The length of the incubation time was inversely related to the number of Prn-p(a) genes in mice inoculated with the Rocky Mountain Laboratory (RML) prion strain. Results with mice lacking this locus (Prn-p0/0) and transgenic mice argue that long incubation times are not a dominant trait as thought for many years, but rather they are due to reduced levels of the substrate PrPC-A (cellular isoform of PrP, allotype A) in (Prn-p(a) x Prn-pb)F1 mice. In contrast, the Prn-p(a) gene extended incubation times in mice inoculated with the 87V and 22A prion strains, whereas the Prn-pb gene was permissive. Experiments with the 87V isolate suggest that a genetic locus distinct from Prn-p controls deposition of the scrapie isoform of PrP (PrPSc) and attendant NeuroPathology. Each prion isolate produced distinguishable patterns of PrPSc accumulation in brain; of note, the patterns in Prn-p(a) and Prn-pb congenic mice inoculated with RML prions were more different than those in congenic Prn-pb mice with RML or 22A prions. Our results suggest that scrapie "strain-specific" incubation times can be explained by differences in the relative efficiency of allotypic interactions that lead to conversion of PrPC into PrPSc. EM - 9409
IS - 0027-8424 LA - English
UI - 94261652 RN - 0 (Prions); 0 (PrPSc Proteins) 


Murine scrapie-infected neurons in vivo release excess prion protein into the extracellular space


NeuroSci Lett 1994 Jun 6;174(1):39-42
Jeffrey M; Goodsir CM; Bruce ME; McBride PA; Fowler N; Scott JR
Lasswade Veterinary Laboratory, Midlothian, Scotland, UK. MJ - Neurons [metabolism]; PrPC Proteins [metabolism]; Prions [metabolism]; Scrapie [metabolism] MN - Brain [microbiology] [pathology]; Extracellular Space [drug effects] [metabolism]; Immunohistochemistry; Mice; Neurons [microbiology] [ultrastructure]; Scrapie [microbiology] [pathology] MT - Animal PT - JOURNAL ARTICLE

An originally heretical proposition that the transmissible spongiform encephalopathies are caused by a host-coded protein (the prion hypothesis) is now current dogma. Indeed these disorders are commonly called prion diseases but the prion hypothesis provides no readily acceptable explanation for the source of the informational component of the agent necessary to code for the diversity of strains of scrapie. Ultrastructural Immunolocalisation of prion protein (PrP) in murine scrapie shows that PrP accumulates in association with the plasmalemma of neurones, diffusing from the neuronal cell surface into the extracellular space around small neurites prior to aggregation and fibril assembly. These events occur without the involvement of other cell types. The area of neuropil infiltrated with extracellular PrP around infected neurons and neurites indicates that the form of PrP initially produced is not immediately amyloidogenic. EM - 9502
IS - 0304-3940 LA - English
UI - 95060196 RN - 0 (Prions); 0 (PrPC Proteins) 


Familial Pick's disease and dementia in frontal lobe degeneration of non-Alzheimer type are not variants of prion disease

[letter]
J Neurol NeuroSurg Psychiatry 1994 Jun;57(6):762
Collinge J; Palmer MS; Sidle KC; Mahal SP; Campbell T; Brown J; Hardy J; Brun AE; Gustafson L; Bakker E; et al MJ - Dementia, Presenile [genetics]; Frontal Lobe; Mutation [genetics]; Prion Diseases [genetics] MN - Brain Diseases [genetics]; Middle Age; Pedigree MT - Case Report; Female; Human PT - LETTER EM - 9409
IS - 0022-3050 LA - English
UI - 94275488 

Inherited prion diseases


Proc Natl Acad Sci USA 1994 May 24;91(11):4611-4
Prusiner SB
Department of Neurology, University of California, San Francisco 94143-0518. MJ - Prion Diseases [genetics]; Prions [genetics] MT - Animal; Human PT - JOURNAL ARTICLE; REVIEW (68 references); REVIEW, TUTORIAL EM - 9409
IS - 0027-8424 LA - English
UI - 94255375 RN - 0 (Prions) 

Rapid anterograde Axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems


J Biol Chem 1994 May 20;269(20):14711-4
Borchelt DR; Koliatsos VE; Guarnieri M; Pardo CA; Sisodia SS; Price DL
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196. MJ - Brain [physiology]; Ganglia, Spinal [physiology]; Nerve Tissue Proteins [metabolism]; Neurons [physiology]; Prions [metabolism]; Sciatic Nerve [physiology] MN - Axonal Transport; Brain [metabolism]; Cell Line; Electrophoresis, Polyacrylamide Gel; Ganglia, Spinal [metabolism]; Hamsters; Mesocricetus; Methionine [metabolism]; Nerve Endings [metabolism] [physiology]; Neurons [metabolism]; Organ Specificity; Prions [biosynthesis] [isolation & purification]; Rabbits [Immunology]; Rats, Sprague-Dawley; Rats; Sciatic Nerve [metabolism]; Sulfur Radioisotopes MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

In prion diseases, the cellular prion protein (PrPc), abundant in neurons, is converted posttranslationally into an amyloid-forming scrapie prion protein (PrPSc), which accumulates in white matter tracts and nerve terminals. The trafficking of PrPc in neurons was investigated in vivo by injecting [35S]methionine into the L4 and L5 dorsal root ganglia and the entorhinal cortices of adult rats and by tracing the movement of radiolabeled PrPc. In both paradigms, labeled 33-35-kDa PrPc was transported, within 4 h, to distal axons and nerve terminals cofractionating with proteins in the fast component. Future studies using these methods may allow us to determine whether PrPc is converted into PrpSc during Axonal transport and whether PrPSc is transported in animals with prion diseases. EM - 9408
IS - 0021-9258 LA - English
UI - 94237891 RN - 0 (Nerve Tissue Proteins); 0 (Prions); 0 (PrPSc Proteins); 0 (Sulfur Radioisotopes); 7005-18-7 (Methionine) ID - AG 05146-AG-NIA; NS 20471-NS-NINDS; NS 10580-NS-NINDS 


[URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae

[see comments] CM - Comment in: Science 1994 Apr 22; 264(5158):528-9
Science 1994 Apr 22;264(5158):566-9
Wickner RB
Section on Genetics of Simple Eukaryotes, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892. MJ - Fungal Proteins [genetics]; Saccharomyces cerevisiae [genetics] MN - Aspartic Acid [analogs & derivatives] [metabolism]; Base Sequence; Crosses, Genetic; Fungal Proteins [chemistry] [metabolism]; Genes, Dominant; Genes, Fungal; Genes, Recessive; Guanidines [pharmacology]; Molecular Sequence Data; Mutation; Phenotype; Plasmids; Prions [chemistry] [genetics] [metabolism]; Saccharomyces cerevisiae [metabolism] PT - JOURNAL ARTICLE

A cytoplasmically inherited element, [URE3], allows yeast to use ureidosuccinate in the presence of ammonium ion. Chromosomal mutations in the URE2 gene produce the same phenotype. [URE3] depends for its propagation on the URE2 product (Ure2p), a negative regulator of enzymes of nitrogen metabolism. Saccharomyces cerevisiae strains cured of [URE3] with guanidium chloride were shown to return to the [URE3]-carrying state without its introduction from other cells. Overproduction of Ure2p increased the frequency with which a strain became [URE3] by 100-fold. In analogy to mammalian prions, [URE3] may be an altered form of Ure2p that is inactive for its normal function but can convert normal Ure2p to the altered form. The genetic evidence presented here suggests that protein-based inheritance, involving a protein unrelated to the mammalian prion protein, can occur in a microorganism. EM - 9407
IS - 0036-8075 LA - English
UI - 94212170 RN - 0 (Fungal Proteins); 0 (Guanidines); 0 (Plasmids); 0 (Prions); 0 (PrPSc Proteins); 113-00-8 (guanidine); 134773-68-5 (URE2 protein); 56-84-8 (Aspartic Acid); 923-37-5 (ureidosuccinic acid) 


Structural clues to prion replication

[see comments] CM - Comment in: Science 1994 Sep 9; 265(5178):1510
Science 1994 Apr 22;264(5158):530-1
Cohen FE; Pan KM; Huang Z; Baldwin M; Fletterick RJ; Prusiner SB
Department of Medicine, University of California, San Francisco 94143-0518. MJ - Prion Diseases [metabolism]; Prions [biosynthesis] MN - Mice, Transgenic; Mice; Models, Biological; Mutation; Prion Diseases [transmission]; Prions [chemistry] [genetics] [metabolism]; Protein Conformation; Protein Structure, Secondary MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE EM - 9407
IS - 0036-8075 LA - English
UI - 94212166 RN - 0 (Prions); 0 (PrPSc Proteins) 

Human prion diseases


Ann Neurol 1994 Apr;35(4):385-95
Prusiner SB; Hsiao KK
Department of Neurology, University of California, San Francisco 94143-0518. MJ - Prion Diseases [genetics] MN - Adult; Aged; Linkage (Genetics); Mice, Transgenic; Mice; Middle Age; Open Reading Frames; Point Mutation; Polymorphism (Genetics); Prions [genetics] MT - Animal; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE; REVIEW (122 references); REVIEW, ACADEMIC

The prion diseases, sometimes referred to as the "transmissible spongiform encephalopathies," include kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker disease of humans as well as scrapie and bovine spongiform encephalopathy of animals. For many years, the prion diseases were thought to be caused by viruses despite intriguing evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve the aberrant metabolism of the prion protein (PrP). In many cases, the cellular prion protein is converted into the scrapie isoform by a posttranslational process that involves a conformational change. Often, the human prion diseases are transmissible to experimental animals and all of the inherited prion diseases segregate with PrP gene mutations. EM - 9407
IS - 0364-5134 LA - English
UI - 94206007 RN - 0 (Prions) ID - NS14069-NS-NINDS; AG08967-AG-NIA; AG02132-AG-NIA; + 


Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism


Proc Natl Acad Sci USA 1994 Mar 29;91(7):2839-42
Monari L; Chen SG; Brown P; Parchi P; Petersen RB; Mikol J; Gray F; Cortelli P; Montagna P; Ghetti B; et al
Division of Neuropathology, Case Western Reserve University, Cleveland, OH 44106. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Insomnia [genetics]; Polymorphism (Genetics); Prion Diseases [genetics]; Prions [genetics] MN - Codon; Peptide Fragments [chemistry]; Phenotype; Prions [chemistry] [drug effects]; Serine Proteinases [metabolism] MT - Comparative Study; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

Fatal familial insomnia and a subtype of Creutzfeldt-Jakob disease, two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asp-178-- Asn) but segregate with different genotypes determined by this mutation and the methionine-valine polymorphism at codon 129 of the prion protein gene. The abnormal isoforms of the prion protein in these two diseases were found to differ both in the relative abundance of glycosylated forms and in the size of the protease-resistant fragments. The size difference was consistent with a different protease cleavage site, suggesting a different conformation of the protease-resistant prion protein present in the two diseases. These differences are likely to be responsible for the type and location of the lesions that characterize these two diseases. Therefore, the combination of the mutation at codon 178 and the polymorphism at codon 129 determines the disease phenotype by producing two altered conformations of the prion protein. EM - 9407
IS - 0027-8424 LA - English
UI - 94195837 RN - EC 3.4.21 (Serine Proteinases); EC 3.4.21.- (Tritirachium alkaline proteinase); 0 (Codon); 0 (Peptide Fragments); 0 (Prions); 0 (PrPSc Proteins) ID - NS-14509-NS-NINDS; NS-29822-NS-NINDS; AG-08012-AG-NIA; + 


Japanese family with Creutzfeldt-Jakob disease with codon 200 point mutation of the prion protein gene


Neurology 1994 Feb;44(2):299-301
Inoue I; Kitamoto T; Doh-ura K; Shii H; Goto I; Tateishi J
Department of Neurology, Kokura-kinen Hospital, Kitakyusyu, Japan. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Point Mutation; Prions [genetics] MN - Adolescence; Adult; Cerebellum [metabolism] [pathology]; Codon; Creutzfeldt-Jakob Syndrome [pathology]; DNA [blood]; Deoxyribonucleases, Type II Site-Specific; Immunohistochemistry; Japan; Lymphocytes [metabolism]; Lysine; Middle Age; Pedigree; Polymerase Chain Reaction; Prions [analysis]; Variation (Genetics) MT - Case Report; Female; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

We report the first Japanese case of familial Creutzfeldt-Jakob disease (CJD) with the heterozygous point mutation at codon 200 of the prion protein gene. This suggests that the mutation is not race-specific. The clinical and pathologic features of this case are not different from those of sporadic CJD without point mutations. Some healthy members of the family also carry the same mutation in the autosomal dominant inheritance expression. EM - 9405
IS - 0028-3878 LA - English
UI - 94142912 RN - EC 3.1.21.- (endodeoxyribonuclease BsmAI); EC 3.1.21.4 (Deoxyribonucleases, Type II Site-Specific); 0 (Codon); 0 (Prions); 0 (PrPSc Proteins); 56-87-1 (Lysine); 9007-49-2 (DNA) 


Prion protein (PrP) is not involved in the PathoGenesis of spongiform encephalopathy in zitter rats


NeuroSci Lett 1994 Jan 31;166(2):171-4
Gomi H; Ikeda T; Kunieda T; Itohara S; Prusiner SB; Yamanouchi K
Institute for Virus Research, Kyoto University, Japan. MJ - Prion Diseases [metabolism]; Prions [metabolism] MN - Amino Acid Sequence; Base Sequence; Blotting, Southern; Blotting, Western; Brain [pathology]; Molecular Sequence Data; Open Reading Frames; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Prion Diseases [genetics]; Rats, Mutant Strains; Rats, Sprague-Dawley; Rats MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

In order to elucidate the relationship between the prion protein (PrP) structure and the development of spongiform encephalopathy in zitter rats, we analyzed the nucleotide sequences and restriction fragment length variation (RFLV) of the Prn gene encoding PrP in zitter rats and inbred SD/J rats as a control. Prn genes from two strains had identical nucleotide sequences in their coding sequences. Obvious RFLV on the locus was not detected in zitter rats by a Southern blot hybridization. Consistently, zitter rat brains express the normal cellular PrP (PrPC), but do not accumulate the protease-resistant modified isoform (PrPSC). These results indicate that PrP is not involved in the PathoGenesis of spongiform encephalopathy in zitter rats. EM - 9408
IS - 0304-3940 LA - English
UI - 94232539 RN - 0 (Prions) SI - GENBANK/S69654 


Insights into the role of the immune system in prion diseases


Proc Natl Acad Sci USA 1994 Jan 18;91(2):429-32
Berg LJ
Department of Cellular and Developmental Biology, Harvard University, Cambridge, MA 02138. MJ - Prion Diseases [Immunology] MN - Immune Tolerance; Prion Diseases [etiology] [transmission]; Prions [genetics] [Immunology] [Pathogenicity]; Scrapie [etiology] [Immunology] MT - Animal; Human PT - JOURNAL ARTICLE; REVIEW (26 references); REVIEW, TUTORIAL EM - 9404
IS - 0027-8424 LA - English
UI - 94119899 RN - 0 (Prions); 0 (PrPSc Proteins) 

Frontal lobe dementia is not a variant of prion disease


NeuroSci Lett 1993 Dec 24;164(1-2):1-4
Clinton J; Mann DM; Roberts GW
Department of Anatomy and Cell Biology, St. Mary's Hospital Medical School, Imperial College, London, UK. MJ - Dementia [pathology]; Frontal Lobe [pathology]; Prion Diseases [pathology] MN - Aged, 80 and over; Aged; Alzheimer's Disease [pathology]; Amyloid beta-Protein [Immunology] [metabolism]; Cerebellum [pathology]; Immunohistochemistry; Middle Age; Tissue Fixation MT - Female; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

Frontal lobe dementia (FLD) is a syndromal diagnosis with a variable pathology. It has been argued that FLD is a dementing disorder which should be nosologically and etiologically distinguished from other types of dementia. However, similarities with prior disease and Alzheimer's disease have led to the suggestion that FLD is a variant of one or other of these dementias. We have tested this line of argument by examining the frontal cortex and cerebellum of 14 FLD cases and probing the molecular pathology using well characterized antibodies to prion protein and beta-amyloid protein. No prion protein deposits or significant levels of beta-amyloid protein were detected. FLD is a dementing disorder whose molecular pathology, whilst as yet uncharacterised, can be distinguished from those of other dementing disorders. EM - 9407
IS - 0304-3940 LA - English
UI - 94203419 RN - 0 (Amyloid beta-Protein) 


Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins


Proc Natl Acad Sci USA 1993 Dec 1;90(23):10962-6
Pan KM; Baldwin M; Nguyen J; Gasset M; Serban A; Groth D; Mehlhorn I; Huang Z; Fletterick RJ; Cohen FE; et al
Department of Neurology, University of California, San Francisco 94143. MJ - Prions [chemistry]; Scrapie [etiology] MN - Circular Dichroism; Hamsters; Immunohistochemistry; Mesocricetus; Microscopy, Electron; Prions [isolation & purification]; Protein Structure, Secondary; Spectroscopy, Fourier Transform Infrared MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

Prions are composed largely, if not entirely, of prion protein (PrPSc in the case of scrapie). Although the formation of PrPSc from the cellular prion protein (PrPC) is a post-translational process, no candidate chemical modification was identified, suggesting that a conformational change features in PrPSc synthesis. To assess this possibility, we purified both PrPC and PrPSc by using nondenaturing procedures and determined the secondary structure of each. Fourier-transform infrared (FTIR) spectroscopy demonstrated that PrPC has a high alpha-helix content (42%) and no beta-sheet (3%), findings that were confirmed by circular dichroism measurements. In contrast, the beta-sheet content of PrPSc was 43% and the alpha-helix 30% as measured by FTIR. As determined in earlier studies, N-terminally truncated PrPSc derived by limited proteolysis, designated PrP 27-30, has an even higher beta-sheet content (54%) and a lower alpha-helix content (21%). Neither PrPC nor PrPSc formed aggregates detectable by electron microscopy, while PrP 27-30 polymerized into rod-shaped amyloids. While the foregoing findings argue that the conversion of alpha-helices into beta-sheets underlies the formation of PrPSc, we cannot eliminate the possibility that an undetected chemical modification of a small fraction of PrPSc initiates this process. Since PrPSc seems to be the only component of the "infectious" prion particle, it is likely that this conformational transition is a fundamental event in the propagation of prions. EM - 9403
IS - 0027-8424 LA - English
UI - 94068524 RN - 0 (Prions); 0 (PrPSc Proteins) 


An Israeli family with Gerstmann-Straussler-Scheinker disease manifesting the codon 102 mutation in the prion protein gene


Neurology 1993 Dec;43(12):2718-9
Goldhammer Y; Gabizon R; Meiner Z; Sadeh M
Department of Neurology, Chaim Sheba Medical Center, Tel Hashomer, Israel. MJ - Codon; Gerstmann-Straussler Syndrome [ethnology] [genetics]; Jews; Mutation; Prions [genetics] MN - Adult; DNA [genetics]; Israel; Pedigree; Polymerase Chain Reaction MT - Case Report; Female; Human PT - JOURNAL ARTICLE

We report the first family among the Jewish population in Israel with Gerstmann-Straussler-Scheinker disease. A proline-for-leucine substitution at the codon 102 of the prion protein (PrP) gene was demonstrated. This mutation has been reported in families with the ataxic form of the disease. EM - 9403
IS - 0028-3878 LA - English
UI - 94077411 RN - 0 (Codon); 0 (Prions); 0 (PrPSc Proteins); 9007-49-2 (DNA) 


A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease


Ann Neurol 1993 Dec;34(6):802-7
Pocchiari M; Salvatore M; Cutruzzola F; Genuardi M; Allocatelli CT; Masullo C; Macchi G; Alema G; Galgani S; Xi YG; et al
Laboratory of Virology, Istituto Superiore di Sanita, Rome, Italy. MJ - Creutzfeldt-Jakob Syndrome [genetics]; Nerve Tissue Proteins [genetics]; Point Mutation; Prions [genetics] MN - Aged, 80 and over; Aged; Base Sequence; Middle Age; Molecular Sequence Data; Open Reading Frames [genetics]; Pedigree MT - Female; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

Complete sequencing of the prion protein open reading frame of a 68-year-old woman affected by a familial form of Creutzfeldt-Jakob disease (CJD) revealed a new mutation at codon 210 resulting in the substitution of isoleucine for valine. Moreover, a new 24-bp deletion encompassing codons 54 to 61 or 62 to 69 was found in the other allele. Four of the 17 asymptomatic relatives tested carry the 210 mutation. Two of them were 81 and 82 years old. Four of 22 patients with CJD whose recorded familial history was negative for demented illnesses, but none of 103 healthy control subjects, tested positive for the 210 mutation. These data suggest that the 210 mutation is associated with CJD, but that environmental factors or incomplete penetrance may contribute to the development of the disease. This finding also suggests that in Italy, familial CJD is more common than previously reported. EM - 9403
IS - 0364-5134 LA - English
UI - 94071412 RN - 0 (Nerve Tissue Proteins); 0 (Prions); 0 (PrPSc Proteins) 


A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesis


Ann Neurol 1993 Dec;34(6):808-13
Kitamoto T; Amano N; Terao Y; Nakazato Y; Isshiki T; Mizutani T; Tateishi J
Department of Neuropathology, Kyushu University, Fukuoka, Japan. MJ - Paraplegia [genetics]; Point Mutation; Prion Diseases [genetics] MN - Adult; Base Sequence; Brain [pathology]; Codon [genetics]; Middle Age; Molecular Sequence Data; Paraplegia [pathology] [physiopathology]; Prion Diseases [pathology] [physiopathology]; Spinal Cord [pathology] MT - Female; Human; Male; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

We report the clinicopathological findings of 5 patients with an inherited prion disease with a codon 105 (Pro to Leu) mutation. All of the patients had a spastic gait disturbance and progressive dementia without either cerebellar signs, myoclonus, or periodic synchronous discharges. Autopsy of 3 patients revealed numerous amyloid plaques in the cerebral cortex, especially in the motor cortex and the frontal lobe where neuronal loss and severe gliosis were observed in the absence of spongiform changes. The cerebellum was preserved histologically except for only a few amyloid plaques. The pyramidal tracts in the brainstem and spinal cord showed vacuolated changes and a loss of myelin, but no prion protein accumulations. Thus, the prion protein codon 105 mutation is considered to correspond to a new variant of the Gerstmann-Straussler syndrome with spastic paraparesis. EM - 9403
IS - 0364-5134 LA - English
UI - 94071413 RN - 0 (Codon)
 


Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies


Proc 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
IS - 0027-8424 LA - English
UI - 94068450 RN - 0 (DNA Primers); 0 (Nerve Tissue Proteins); 0 (Prions); 0 (PrPSc Proteins) 


Genetic and infectious prion diseases


Arch 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
IS - 0003-9942 LA - English
UI - 94029646 RN - 0 (Prions); 0 (PrPSc Proteins) ID - NS14069-NS-NINDS; AG08967-AG-NIA; AG02132-AG-NIA; + 


Accumulation of abnormal prion protein in mice infected with Creutzfeldt-Jakob disease via intraperitoneal route: a sequential study


Am 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
IS - 0002-9440 LA - English
UI - 94056669 RN - 0 (Prions) 


Scrapie prions alter receptor-mediated calcium responses in cultured cells


Neurology 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
IS - 0028-3878 LA - English
UI - 94050627 RN - 0 (Calcium Channels); 0 (Prions); 0 (Receptors, Cell Surface); 58-82-2 (Bradykinin); 7440-70-2 (Calcium) ID - AG02132-AG-NIA; NS14069-NS-NINDS; NS22786-NS-NINDS; + 


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 polymorphism


Am 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
IS - 0002-9297 LA - English
UI - 94027047 RN - 0 (Codon); 0 (Nerve Tissue Proteins); 0 (Prions); 0 (PrPSc Proteins) 


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 junctions


NeuroSci 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
IS - 0304-3940 LA - English
UI - 94088919 RN - 0 (Antibodies, Monoclonal); 0 (Bungarotoxins); 0 (Prions); 0 (Receptors, Cholinergic) 


A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells

J Biol Chem 1993 Jul 25;268(21):15922-8
Shyng SL; Huber MT; Harris DA
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110. MJ - Cell Membrane [metabolism]; Endocytosis; Prions [metabolism] MN - Biological Transport; Cell Compartmentation; Chickens; Cyclopentanes [pharmacology]; Hydrolysis; Iodine [chemistry]; Lysosomes [drug effects]; Mice; Microscopy, Fluorescence; Neuroblastoma; Prions [biosynthesis] [chemistry]; Tumor Cells, Cultured MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

The prion protein (PrPC) is a glycolipid-anchored, cell surface protein of unknown function, a posttranslationally modified isoform of which has been implicated in the PathoGenesis of spongiform encephalopathies in man and animals. We report here the novel observation that chPrP, the chicken homologue of mammalian PrPC, constitutively cycles between the cell surface and an endocytic compartment with a transit time of approximately 60 min, as demonstrated by surface iodination and Immunofluorescence microscopy. Most ( 95%) of the internalized protein is returned to the cell surface intact, and the remainder is proteolytically cleaved within a highly conserved region in the NH2-terminal half of the molecule. Pulse-chase labeling experiments indicate that while this cleavage is slow, with a rate of approximately 1%/h, the COOH-terminal fragment produced is stable and accumulates on the cell surface for as long as 24 h. The cleavage is likely to take place in an acidified endocytic compartment, since it is reduced by lysosomotropic amines and inhibitors of lysosomal proteases. Our results raise the possibility that chPrP, and perhaps other PrPCs, function as Cell Surface Receptors, and they suggest cellular pathways that might be involved in the generation of the Pathogenic isoform.

EM - 9311
IS - 0021-9258 LA - English
UI - 93340202 RN - 0 (Cyclopentanes); 0 (Prions); 0 (PrPSc Proteins); 7553-56-2 (Iodine); 84277-18-9 (brefeldin A) ID - NS30137-NS-NINDS

Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform

Proc Natl Acad Sci USA 1993 Jul 15;90(14):6449-53
De Armond SJ; Yang SL; Lee A; Bowler R; Taraboulos A; Groth D; Prusiner SB
Department of Pathology, University of California, San Francisco 94143. MJ - Brain [pathology]; Prions [genetics]; Scrapie [genetics]; Variation (Genetics) MN - Hamsters; Immunohistochemistry; Mesocricetus; Mice, Transgenic; Mice; Prions [isolation & purification]; Scrapie [etiology]; Tissue Distribution MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

To investigate the molecular basis of prion diversity, we inoculated transgenic mice expressing the Syrian hamster prion protein (PrP) with three distinct prion isolates. We compared the three isolates designated Sc237, 139H, and Me7H in Tg(SHaPrP)7 mice with clinical signs of scrapie because the incubation times with these mice are considerably shorter than the times found with hamsters. Each prion isolate produced a distinctive pattern of the scrapie isoform of PrP (PrPSc) accumulation, as determined by histoblotting, a technique developed for the regional mapping of PrPSc deposition. The PrPSc pattern with the Me7H isolate was particularly interesting because it appeared to be confined to the hypothalamus and related structures--including the interstitial nucleus of the stria terminalis, the paraventricular nucleus of the thalamus, and periaqueductal grey. Additionally, the regions of PrPSc accumulation remained highly restricted, even though the incubation time for Me7H scrapie was significantly longer than with Sc237 and 139H isolates. Neuropathological changes characterized by neuronal vacuolation and astrocytic gliosis were confined to those regions where PrPSc accumulated. These findings argue that the cell-specific propagation of prion isolates may be responsible for different properties exhibited by each of the isolates.

EM - 9311
IS - 0027-8424 LA - English
UI - 93342009 RN - 0 (Prions); 0 (PrPSc Proteins) ID - AG02132-AG-NIA; AG08967-AG-NIA; NS14069-NS-NINDS

Alzheimer disease and the prion disorders amyloid beta-protein and prion protein amyloidoses

[published erratum appears in Proc Natl Acad Sci USA 1993 Oct 1; 90(19):9233]
Proc Natl Acad Sci USA 1993 Jul 15;90(14):6381-4
Price DL; Borchelt DR; Sisodia SS
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196. MJ - Alzheimer's Disease; Amyloid beta-Protein [metabolism]; Amyloidosis [pathology]; Prion Diseases; Prions [metabolism] MN - Alzheimer's Disease [genetics] [metabolism] [pathology]; Prion Diseases [genetics] [metabolism] [pathology] MT - Comparative Study; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE; REVIEW (99 references); REVIEW, ACADEMIC

Alzheimer disease and the prion disorders/spongiform encephalopathies share many common features. These chronic, progressive, sometimes familial diseases of the central nervous system are characterized by the presence of different types of amyloid deposits in the brain. This review provides a perspective on these two types of neurodegenerative disorders.

EM - 9311
IS - 0027-8424 LA - English
UI - 93341995 RN - 0 (Amyloid beta-Protein); 0 (Prions); 0 (PrPSc Proteins) ID - AG 05146-AG-NIA; NS 07179-NS-NINDS; NS 20471-NS-NINDS; +

A kinetic model for amyloid formation in the prion diseases: importance of seeding


Proc Natl Acad Sci USA 1993 Jul 1;90(13):5959-63
Come JH; Fraser PE; Lansbury PT Jr
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139. MJ - Amyloid [biosynthesis]; Prion Diseases [metabolism] MN - Alzheimer's Disease [metabolism]; Amino Acid Sequence; Amyloid [chemistry]; Models, Biological; Molecular Sequence Data; Peptide Fragments [chemistry]; Prions [metabolism]; Thermodynamics; Virus Replication MT - Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

The transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases characterized by amyloid formation in the brain. The major amyloid protein is the prion protein (PrP). PrP and the beta-amyloid protein of Alzheimer disease share a similar sequence that, in both cases, may be responsible for the initiation of protein aggregation in vivo. We report here that a peptide based on this sequence in PrP (PrP96-111M) forms amyloid fibrils. The existence of a kinetic barrier to amyloid formation by this peptide was demonstrated, suggesting that formation of an ordered nucleus is the rate-determining step for aggregation. Seeding was demonstrated to occur with PrP96-111M amyloid fibrils but not with amyloid fibrils of a related peptide. This effect is consistent with the proposal that the aggregation of PrP, which characterizes TSE, involves a nucleation event analogous to the seeding of a crystallization.

EM - 9310
IS - 0027-8424 LA - English
UI - 93317603 RN - 0 (Amyloid); 0 (Peptide Fragments); 0 (Prions)

Dementia associated with a 216 base pair insertion in the prion protein gene. Clinical and NeuroPathological features

Brain 1993 Jun;116 ( Pt 3):555-67
Duchen LW; Poulter M; Harding AE
Department of Neuropathology, Institute of Neurology and The National Hospital for Neurology, London, UK. MJ - Brain [pathology]; Dementia [pathology]; Mutation; Prion Diseases [pathology]; Prions [genetics] MN - Basal Ganglia [pathology]; Base Sequence; Cerebellum [pathology]; Dementia [genetics]; Middle Age; Prion Diseases [genetics] MT - Case Report; Female; Human; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

We report the clinical and NeuroPathological findings in a patient with a 216 base pair insertion in the prion protein (PrP) gene. She died aged 57 years after a 2.5-year illness characterized by falls, axial rigidity, myoclonic jerks and progressive dementia. There was no history of affected relatives. The pathological changes consisted of the deposition in cerebellum, basal ganglia and cortex of small plaques composed of variable amounts of amyloid and degenerative material which was associated with a marked macrophage reaction. The amyloid deposits in the cerebellum and basal ganglia gave a positive Immunoperoxidase staining reaction for PrP. In some places plaques bore a resemblance to senile neuritic plaques and in the hippocampus there were abundant typical neuritic plaques giving positive staining reactions for beta-amyloid protein and tau protein, but not PrP. There were few neurons bearing neurofibrillary tangles. This is the first report of the NeuroPathological changes associated with this particular abnormality of the PrP gene and it seems to demonstrate a transition between the pathology of prion disease and that of Alzheimer's disease. The importance of PrP gene analysis to the understanding of neurodegenerative diseases is stressed.

EM - 9309
IS - 0006-8950 LA - English
UI - 93291952 RN - 0 (Prions)

Biology of prion diseases

J Acquir Immune Defic Syndr 1993 Jun;6(6):663-5
Prusiner SB
Department of Neurology, University of California, San Francisco 94143-0518. MJ - Prion Diseases MN - Biology; Mice, Transgenic; Mice; Prion Diseases [genetics] [microbiology] [pathology] MT - Animal; Human PT - JOURNAL ARTICLE; REVIEW (30 references); REVIEW, TUTORIAL EM - 9308
IS - 0894-9255 LA - English
UI - 93267408

Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells

Proc Natl Acad Sci USA 1993 Apr 15;90(8):3182-6
Rogers M; Yehiely F; Scott M; Prusiner SB
Department of Neurology, University of California, San Francisco 94143. MJ - Genes, Viral; Prions [genetics] [metabolism] MN - Amino Acid Sequence; Base Sequence; Chimera; Glycosylphosphatidylinositols [analysis]; Hamsters; Mesocricetus; Mice; Molecular Sequence Data; Neuroblastoma; Oligodeoxyribonucleotides; Prions [isolation & purification]; Recombination, Genetic; Repetitive Sequences, Nucleic Acid; Restriction Mapping; Tumor Cells, Cultured MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

The only known component of the infectious prion is a posttranslationally modified protein known as the scrapie isoform of the prion protein, PrPSc. Upon limited proteolysis, a protease-resistant fragment designated PrP 27-30 is formed. Using in vitro mutagenesis, we examined the role of the N and C termini in the formation of PrPSc in persistently infected, mouse neuroblastoma (ScN2a) cells. Neither deletion of amino acids 23-88, which are also removed by proteinase K in the formation of PrP 27-30, nor deletion of the five octapeptide repeats within this region altered synthesis of PrPSc. Elongation of PrP with one, two, four, or six octapeptide repeats in addition to the five found in wild-type PrP did not alter the synthesis of PrPSc. Truncation of the C terminus was accomplished by substituting a translation stop codon for the predicted glycosylinositol phospholipid (GPI) anchor-attachment signal corresponding to amino acids 231-254. Expression of this C-terminal PrP mutant in ScN2a cells produced PrPSc that appeared to lack a GPI anchor. We conclude that neither the GPI anchor nor the N-terminal 66 amino acids are required for the synthesis of PrPSc as measured by the acquisition of limited resistance to proteinase K digestion. Whether these truncated or elongated PrP molecules are competent to participate in the formation of infectious prions remains to be established.

EM - 9307
IS - 0027-8424 LA - English
UI - 93234460 RN - 0 (Glycosylphosphatidylinositols); 0 (Oligodeoxyribonucleotides); 0 (Prions) ID - AG02132-AG-NIA; NS14069-NS-NINDS; AG08967-AG-NIA; +

Neurotoxicity of a prion protein fragment

Nature 1993 Apr 8;362(6420):543-6
Forloni G; Angeretti N; Chiesa R; Monzani E; Salmona M; Bugiani O; Tagliavini F
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. MJ - Neurons [drug effects]; Peptide Fragments [toxicity]; Prions [toxicity] MN - Amino Acid Sequence; Apoptosis; Cells, Cultured; Dose-Response Relationship, Drug; Hippocampus [cytology] [metabolism]; Molecular Sequence Data; Peptide Fragments [genetics]; Rats MT - Animal; Support, Non-U.S. Gov't PT - JOURNAL ARTICLE

The cellular prion protein (PrPC) is a sialoglycoprotein of M(r) 33-35K that is expressed predominantly in neurons. In transmissible and genetic neurodegenerative disorders such as scrapie of sheep, spongiform encephalopathy of cattle and Creutzfeldt-Jakob or Gerstmann-Straussler-Scheinker diseases of humans, PrPC is converted into an altered form (termed PrPSc) which is distinguishable from its normal homologue by its relative resistance to protease digestion. PrPSc accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates extracellularly into amyloid fibrils. The process is accompanied by nerve cell loss, whose PathoGenesis and molecular basis are not understood. We report here that neuronal death results from chronic exposure of primary rat hippocampal cultures to micromolar concentrations of a peptide corresponding to residues 106-126 of the amino-acid sequence deduced from human PrP complementary DNA. DNA fragmentation of degenerating neurons indicates that cell death occurred by apoptosis. The PrP peptide 106-126 has a high intrinsic ability to polymerize into amyloid-like fibrils in vitro. These findings indicate that cerebral accumulation of PrPSc and its degradation products may play a role in the nerve cell degeneration that occurs in prion-related encephalopathies.

EM - 9307
IS - 0028-0836 LA - English
UI - 93218742 RN - 0 (Peptide Fragments); 0 (Prions)

Attempts to restore scrapie prion infectivity after exposure to protein denaturants

Proc Natl Acad Sci USA 1993 Apr 1;90(7):2793-7
Prusiner SB; Groth D; Serban A; Stahl N; Gabizon R
Department of Neurology, University of California, San Francisco 94143. MJ - Phospholipids [pharmacology]; Prions [drug effects] [Pathogenicity]; Urea [pharmacology] MN - Brain [microbiology]; Electrophoresis, Polyacrylamide Gel; Hamsters; Kinetics; Mesocricetus; Prions [isolation & purification]; Protein Denaturation MT - Animal; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S. PT - JOURNAL ARTICLE

A wealth of experimental evidence argues that infectious prions are composed largely, if not entirely, of the scrapie isoform of the prion protein. We attempted to restore scrapie infectivity after exposure to protein denaturants including urea, chaotropic salts, and SDS. None of the procedures restored infectivity. Dialysis to remove slowly chaotropic ions and urea failed to restore scrapie infectivity. Attempts to create monomers of the scrapie isoform of the prion protein under nondenaturing conditions using a wide variety of detergents have been unsuccessful, to date, except for one report claiming that scrapie infectivity could be recovered from 12% polyacrylamide gels after SDS/PAGE [Brown, P., Liberski, P. P., Wolff, A. & Gajdusek, D. C. (1990) Proc. Natl. Acad. Sci. USA 87, 7240-7244]. We found that 0.001% of the infectious prion titer could be recovered from the region of a polyacrylamide gel where the denatured proteinase K-resistant core of the scrapie isoform of the prion protein and other 30-kDa proteins migrate. We conclude that under the denaturing conditions used for SDS/PAGE, the scrapie isoform of the prion protein is denatured and little or no renaturation occurs upon injection of fractions eluted from gels into animals for bioassays.

EM - 9307
IS - 0027-8424 LA - English
UI - 93219370 RN - 0 (Phospholipids); 0 (Prions); 57-13-6 (Urea) ID - AG02132-AG-NIA; NS14069-NS-NINDS; AG08967-AG-NIA; + 

Spending on BSE research

[letter]
Nature 1996 Sep 19;383(6597):211
Schellekens H MJ - Encephalopathy, Bovine Spongiform [transmission] MN - Cattle; Chimpansee troglodytes; Food Contamination; Great Britain; Meat; Prions [Pathogenicity]; Risk Factors; Species Specificity MT - Animal; Human PT - LETTER EM - 9612
IS - 0028-0836 LA - English
UI - 96399118 RN - 0 (Prions)

  


Abbreviations...

 

  • "IS" = ISSN number
  • "UI" = Unique NLM Identifier



If you've gotten this far and would like the additional 155 abstracts (Hee-Hee)....Let me know when you are finished with this. I will wipe this off my hard drive to free up the additional space, then post more of the abstracts. It will be the same URL. I will copy and paste the information into this pre-existing page.
 
This is some pretty fascinating information Tom, WOW ! Hmmmnnn.....
 
The graphic below has been set up as a mailbox...The graphic depicts is my rendition of how I feel when MS is giving me a hard time. You know, when you feel like you're sort of "fading in and out". Hey I resemble that statement, er I mean I can relate to that :D
 
Kim Levinson :-)
Type to you later, yah, yah... I stole that phrase from you! KimLev O :D
 

Tripod HomePage ThJuland's MSers' Glen - Our CyberHome To Page Top The Glen's Gallery: Come & Share Our Stories MS Files MS Abstracts Site Index


Copyright 1997 - 2010:
Permission is granted to MS Societies and all MSers to utilize information from these pages provided that no financial reward is gained and attribution is given to the author/s.