Quinacrine promotes replication and conformational mutation of chronic wasting disease prions.

Abstract:

:Quinacrine's ability to reduce levels of pathogenic prion protein (PrP(Sc)) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP(Sc) accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP(Sc) deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP(Sc) conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.

authors

Bian J,Kang HE,Telling GC

doi

10.1073/pnas.1322377111

subject

Has Abstract

pub_date

2014-04-22 00:00:00

pages

6028-33

issue

16

eissn

0027-8424

issn

1091-6490

pii

1322377111

journal_volume

111

pub_type

杂志文章
  • Enzyme null alleles in natural populations of Drosophila melanogaster: Frequencies in a North Carolina population.

    abstract::A Raleigh, NC, population of Drosophila melanogaster was sampled for the presence of enzyme null alleles at 25 loci. No nulls were found at any of five X-linked loci. Nulls were recovered at 13 of 20 autosomal loci; the weighted mean frequency for all 20 autosomal loci was estimated to be 0.0025. A consideration of th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.2.1091

    authors: Voelker RA,Langley CH,Brown AJ,Ohnishi S,Dickson B,Montgomery E,Smith SC

    更新日期:1980-02-01 00:00:00

  • Hsp104 disaggregase at normal levels cures many [PSI+] prion variants in a process promoted by Sti1p, Hsp90, and Sis1p.

    abstract::Overproduction or deficiency of many chaperones and other cellular components cure the yeast prions [PSI+] (formed by Sup35p) or [URE3] (based on Ure2p). However, at normal expression levels, Btn2p and Cur1p eliminate most newly arising [URE3] variants but do not cure [PSI+], even after overexpression. Deficiency or o...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1704016114

    authors: Gorkovskiy A,Reidy M,Masison DC,Wickner RB

    更新日期:2017-05-23 00:00:00

  • Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI.

    abstract::Recent functional imaging studies have revealed coactivation in a distributed network of cortical regions that characterizes the resting state, or default mode, of the human brain. Among the brain regions implicated in this network, several, including the posterior cingulate cortex and inferior parietal lobes, have al...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0308627101

    authors: Greicius MD,Srivastava G,Reiss AL,Menon V

    更新日期:2004-03-30 00:00:00

  • Additional component in the cellular mechanism of presynaptic facilitation contributes to behavioral dishabituation in Aplysia.

    abstract::Sensitization of defensive gill and siphon withdrawal reflexes in Aplysia results, in part, from presynaptic facilitation of transmitter release from mechanoreceptor sensory neurons that innervate the siphon skin and synapse with interneurons and motor neurons. Presynaptic facilitation also can be elicited by applicat...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.22.8794

    authors: Hochner B,Klein M,Schacher S,Kandel ER

    更新日期:1986-11-01 00:00:00

  • Statistical energy conservation principle for inhomogeneous turbulent dynamical systems.

    abstract::Understanding the complexity of anisotropic turbulent processes over a wide range of spatiotemporal scales in engineering shear turbulence as well as climate atmosphere ocean science is a grand challenge of contemporary science with important societal impact. In such inhomogeneous turbulent dynamical systems there is ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1510465112

    authors: Majda AJ

    更新日期:2015-07-21 00:00:00

  • Membrane potential changes caused by thyrotropin-releasing hormone in the clonal GH3 cell and their relationship to secretion of pituitary hormone.

    abstract::Effects of thyrotropin-releasing hormone (TRH; thyroliberin) on membrane electrical properties were studied in the clonal rat anterior pituitary cell (GH3) by continuous recording of the intracellular potential. Application of TRH, which stimulates the release of prolactin and growth hormone from the GH3 cell, elicite...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.11.6017

    authors: Ozawa S,Kimura N

    更新日期:1979-11-01 00:00:00

  • Molecular cloning of human terminal deoxynucleotidyltransferase.

    abstract::A cDNA of the human terminal deoxynucleotidyltransferase (TdT; "terminal transferase," EC 2.7.7.31) was isolated from a human lymphoblastoid cell cDNA library in lambda gt 11 by using immunological procedures. Four inserts containing 723 to 939 base pairs were recloned in pBR322 for hybridization and preliminary seque...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.14.4363

    authors: Peterson RC,Cheung LC,Mattaliano RJ,Chang LM,Bollum FJ

    更新日期:1984-07-01 00:00:00

  • Wide distribution of immunoreactive renin in nerve cells of human brain.

    abstract::By use of the indirect peroxidase-antiperoxidase complex immunocytochemical technique, antibody to purified human renal renin was applied to formalin-fixed paraffin sections of human cadaver brain. Immune reaction products were observed in most nerve cells in all areas of the brain examined; staining was limited to th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.9.5458

    authors: Slater EE,Defendini R,Zimmerman EA

    更新日期:1980-09-01 00:00:00

  • Bursting electrical activity in pancreatic beta cells caused by Ca(2+)- and voltage-inactivated Ca2+ channels.

    abstract::We investigate the hypothesis that two classes of Ca2+ currents, one quickly inactivated by Ca2+ and one slowly inactivated by voltage, contribute to bursting electrical activity in pancreatic islets. A mathematical model of these currents is fit to the experimental whole-cell current-voltage and inactivation profiles...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.9.3897

    authors: Keizer J,Smolen P

    更新日期:1991-05-01 00:00:00

  • Isolation and characterization of adult bovine heart muscle chalones.

    abstract::A three-step purification procedure for the isolation of heart muscle chalones is described. The method uses ultrafiltration followed by concanavalin A-Sepharose affinity chromatography and subsequent sucrose density gradient centrifugation. Analytical ultracentrifugation of the highly purified chalone fraction indica...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.7.4161

    authors: Kriek JA,van der Walt BJ,Bester AJ

    更新日期:1981-07-01 00:00:00

  • Use of a lipophilic cation for determination of membrane potential in neuroblastoma-glioma hybrid cell suspensions.

    abstract::Neuroblastoma-glioma hybrid cells (NG108-15) in suspension accumulate the permeant lipophilic cation [(3)H]tetraphenylphosphonium (TPP(+)) against a concentration gradient. The steady-state level of TPP(+) accumulation is about twice as great in physiological media of low K(+) concentration (i.e., 5 mM K(+)/135 mM Na(...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.2.650

    authors: Lichtshtein D,Kaback HR,Blume AJ

    更新日期:1979-02-01 00:00:00

  • Measures of residue density in protein structures.

    abstract::A hierarchy of residue density assessments and packing properties in protein structures are contrasted, including a regular density, a variety of charge densities, a hydrophobic density, a polar density, and an aromatic density. These densities are investigated by alternative distance measures and also at the interfac...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.22.12494

    authors: Baud F,Karlin S

    更新日期:1999-10-26 00:00:00

  • Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease.

    abstract::Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-β (Aβ) plaque-enriched regions. However, it has remained unknown what com...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1206171109

    authors: Busche MA,Chen X,Henning HA,Reichwald J,Staufenbiel M,Sakmann B,Konnerth A

    更新日期:2012-05-29 00:00:00

  • Species diversity concurrently dilutes and amplifies transmission in a zoonotic host-pathogen system through competing mechanisms.

    abstract::In this era of unprecedented biodiversity loss and increased zoonotic disease emergence, it is imperative to understand the effects of biodiversity on zoonotic pathogen dynamics in wildlife. Whether increasing biodiversity should lead to a decrease or increase in infection prevalence, termed the dilution and amplifica...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1807106115

    authors: Luis AD,Kuenzi AJ,Mills JN

    更新日期:2018-07-31 00:00:00

  • Inhibition of cellular protein synthesis by double-stranded RNA: inactivation of an initiation factor.

    abstract::Inhibition of protein synthesis in rabbit reticulocyte lysates by double-stranded RNA is caused by the inactivation of IF-3, an initiation factor required for the recycling of ribosomes and for their binding to messenger RNA. The evidence for this is that (i) the inhibition can be overcome by addition of exogenous If-...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.70.4.1222

    authors: Kaempfer R,Kaufman J

    更新日期:1973-04-01 00:00:00

  • Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone.

    abstract::Antagonists of growth hormone-releasing hormone (GHRH) inhibit the proliferation of various human cancers in vitro and in vivo by mechanisms that include apparent direct effects through specific binding sites expressed on tumors and that differ from pituitary human GHRH (hGHRH) receptors. In this study, GHRH antagonis...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.180313097

    authors: Halmos G,Schally AV,Varga JL,Plonowski A,Rekasi Z,Czompoly T

    更新日期:2000-09-12 00:00:00

  • Coenzyme Q10 prevents peripheral neuropathy and attenuates neuron loss in the db-/db- mouse, a type 2 diabetes model.

    abstract::Diabetic peripheral neuropathy (DPN) is the most common complication in both type 1 and type 2 diabetes. Here we studied some phenotypic features of a well-established animal model of type 2 diabetes, the leptin receptor-deficient db(-)/db(-) mouse, and also the effect of long-term (6 mo) treatment with coenzyme Q10 (...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1220794110

    authors: Shi TJ,Zhang MD,Zeberg H,Nilsson J,Grünler J,Liu SX,Xiang Q,Persson J,Fried KJ,Catrina SB,Watanabe M,Arhem P,Brismar K,Hökfelt TG

    更新日期:2013-01-08 00:00:00

  • Mantle cell lymphoma is characterized by inactivation of the ATM gene.

    abstract::In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Recently, however, deletion of the chromosomal region 11q22-q23 has been identified as a frequent event in this type of cancer, indicating the existence of a pathogenically relevant tumor suppressor gene in...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.050400997

    authors: Schaffner C,Idler I,Stilgenbauer S,Döhner H,Lichter P

    更新日期:2000-03-14 00:00:00

  • Expression profiling of pancreatic beta cells: glucose regulation of secretory and metabolic pathway genes.

    abstract::Pancreatic beta cells respond to changes in blood glucose by secreting insulin and increasing insulin synthesis. To identify genes used in these responses, we have carried out expression profiling of beta cells exposed to high (25 mM) or low (5.5 mM) glucose by using oligonucleotide microarrays. Functional clustering ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.100126597

    authors: Webb GC,Akbar MS,Zhao C,Steiner DF

    更新日期:2000-05-23 00:00:00

  • Intermolecular associations determine the dynamics of the circadian KaiABC oscillator.

    abstract::Three proteins from cyanobacteria (KaiA, KaiB, and KaiC) can reconstitute circadian oscillations in vitro. At least three molecular properties oscillate during this reaction, namely rhythmic phosphorylation of KaiC, ATP hydrolytic activity of KaiC, and assembly/disassembly of intermolecular complexes among KaiA, KaiB,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1002119107

    authors: Qin X,Byrne M,Mori T,Zou P,Williams DR,McHaourab H,Johnson CH

    更新日期:2010-08-17 00:00:00

  • Molecular basis of transabdominal--a sexually dimorphic mutant of the bithorax complex of Drosophila.

    abstract::Transabdominal (Tab) is a dominant gain-of-function mutation that results in islands of sexually dimorphic abdominal cuticle in the dorsal thorax of the adult fly. This phenotype has complete penetrance and constant expressivity, and we show that it results from ectopic expression of ABD-BII, one of two proteins deriv...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.4.1566

    authors: Celniker SE,Lewis EB

    更新日期:1993-02-15 00:00:00

  • Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching.

    abstract::The switch from fetal to adult hemoglobin expression is regulated in many mammalian species by a developmental clock-like mechanism and determined by the gestational age of the fetus. Prolonging fetal globin gene expression is of considerable interest for therapeutic potential in diseases caused by abnormal beta-globi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.22.8540

    authors: Perrine SP,Rudolph A,Faller DV,Roman C,Cohen RA,Chen SJ,Kan YW

    更新日期:1988-11-01 00:00:00

  • Theoretical studies of the conformational properties of ribavirin.

    abstract::One of the factors required for the antiviral activity of the synthetic nucleoside, ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), is the ability of the molecule to adopt the substrate conformation specified by the enzyme for which it is a competitive inhibitor, inosine 5'-phosphate dehydrogenase (IM...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.12.4257

    authors: Miles DL,Miles DW,Redington P,Eyring H

    更新日期:1976-12-01 00:00:00

  • Calcium currents recorded from a vertebrate presynaptic nerve terminal are resistant to the dihydropyridine nifedipine.

    abstract::The influx of Ca ions into the presynaptic nerve terminal through ion channels is a key link between the action potential and the release of chemical transmitters. It is not clear, however, which types of Ca channel are involved in neurosecretion at vertebrate synapses. In particular, there is disagreement as to wheth...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.24.9683

    authors: Stanley EF,Atrakchi AH

    更新日期:1990-12-01 00:00:00

  • Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away.

    abstract::A central tenet in understanding the biological effects of ionizing radiation has been that the initially affected cells were directly damaged by the radiation. By contrast, evidence has emerged concerning "bystander" responses involving damage to nearby cells that were not themselves directly traversed by the radiati...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0505020102

    authors: Belyakov OV,Mitchell SA,Parikh D,Randers-Pehrson G,Marino SA,Amundson SA,Geard CR,Brenner DJ

    更新日期:2005-10-04 00:00:00

  • Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin.

    abstract::DNA was prepared from 15 different mouse and rat cell lines transformed by chemical carcinogens in vitro and in vivo. These DNAs were applied to NIH3T3 mouse fibroblast cultures by using the calcium phosphate transfection technique. DNAs of five donor lines were able to induce foci on the recipient monolayers. Ten oth...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.11.5714

    authors: Shih C,Shilo BZ,Goldfarb MP,Dannenberg A,Weinberg RA

    更新日期:1979-11-01 00:00:00

  • Growth-and density-dependent inhibition of deoxyglucose transport in Balb 3T3 cells and its absence in cells transformed by murine sarcoma virus.

    abstract::The earliest measurable parameter that shows density-dependent inhibition is the uptake of [(3)H]deoxyglucose by Balb 3T3 cells. The rate decreases even during the exponential phase of growth and reaches a minimum, about 8- to 10-times lower than maximum, as the culture approaches the saturation density. Cells transfo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.70.8.2374

    authors: Bose SK,Zlotnick BJ

    更新日期:1973-08-01 00:00:00

  • Changes in type of collagen synthesized as clones of chick chondrocytes grow and eventually lose division capacity.

    abstract::Clones of embryonic chick chondrocytes have been isolated and collagen biosynthesis has been followed as the clones grow and eventually lose division capacity. Analysis of collagen type at each successive subculture until the time of cellular senescence has shown that a change in synthesis occurs from the cartilage-sp...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.5.1674

    authors: Mayne R,Vail MS,Mayne PM,Miller EJ

    更新日期:1976-05-01 00:00:00

  • Isolation and characterization of a cDNA coding for human factor IX.

    abstract::A cDNA library prepared from human liver has been screened for factor IX (Christmas factor), a clotting factor that participates in the middle phase of blood coagulation. The library was screened with a single-stranded DNA prepared from enriched mRNA for baboon factor IX and a synthetic oligonucleotide mixture. A plas...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.21.6461

    authors: Kurachi K,Davie EW

    更新日期:1982-11-01 00:00:00

  • Identification of human genomic clones coding the major histocompatibility antigens HLA-a2 and HLA-B7 by DNA-mediated gene transfer.

    abstract::We have screened a large number of isolated human genomic clones that hybridize to a cloned HLA cDNA probe for their ability to direct the synthesis of HLA-A, -B, and -C surface antigens on mouse L cells following DNA-mediated gene transfer. The surface expression of human histocompatibility antigens, monitored by ind...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.20.6327

    authors: Barbosa JA,Kamarck ME,Biro PA,Weissman SM,Ruddle FH

    更新日期:1982-10-01 00:00:00