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.
journal_name
Proc Natl Acad Sci U S Aauthors
Bian J,Kang HE,Telling GCdoi
10.1073/pnas.1322377111subject
Has Abstractpub_date
2014-04-22 00:00:00pages
6028-33issue
16eissn
0027-8424issn
1091-6490pii
1322377111journal_volume
111pub_type
杂志文章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
更新日期:1980-02-01 00:00:00
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
更新日期:2017-05-23 00:00:00
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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
更新日期:2004-03-30 00:00:00
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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
更新日期:1986-11-01 00:00:00
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
更新日期:2015-07-21 00:00:00
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
更新日期:1979-11-01 00:00:00
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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
更新日期:1984-07-01 00:00:00
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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
更新日期:1980-09-01 00:00:00
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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
更新日期:1991-05-01 00:00:00
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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
更新日期:1981-07-01 00:00:00
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
更新日期:1979-02-01 00:00:00
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
更新日期:1999-10-26 00:00:00
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
更新日期:2012-05-29 00:00:00
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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
更新日期:2018-07-31 00:00:00
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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
更新日期:1973-04-01 00:00:00
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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
更新日期:2000-09-12 00:00:00
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
更新日期:2013-01-08 00:00:00
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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
更新日期:2000-03-14 00:00:00
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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
更新日期:2000-05-23 00:00:00
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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
更新日期:2010-08-17 00:00:00
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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
更新日期:1993-02-15 00:00:00
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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
更新日期:1988-11-01 00:00:00
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
更新日期:1976-12-01 00:00:00
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
更新日期:1990-12-01 00:00:00
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
更新日期:2005-10-04 00:00:00
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
更新日期:1979-11-01 00:00:00
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
更新日期:1973-08-01 00:00:00
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
更新日期:1976-05-01 00:00:00
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
更新日期:1982-11-01 00:00:00
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
更新日期:1982-10-01 00:00:00