Publications by authors named "Timothy D Kurt"

16 Publications

  • Page 1 of 1

Key Considerations for the Use of Seaweed to Reduce Enteric Methane Emissions From Cattle.

Front Vet Sci 2020 23;7:597430. Epub 2020 Dec 23.

Foundation for Food and Agriculture Research, Washington, DC, United States.

Enteric methane emissions are the single largest source of direct greenhouse gas emissions (GHG) in beef and dairy value chains and a substantial contributor to anthropogenic methane emissions globally. In late 2019, the World Wildlife Fund (WWF), the Advanced Research Projects Agency-Energy (ARPA-E) and the Foundation for Food and Agriculture Research (FFAR) convened approximately 50 stakeholders representing research and production of seaweeds, animal feeds, dairy cattle, and beef and dairy foods to discuss challenges and opportunities associated with the use of seaweed-based ingredients to reduce enteric methane emissions. This article describes the considerations identified by the workshop participants and suggests next steps for the further development and evaluation of seaweed-based feed ingredients as enteric methane mitigants. Although numerous compounds derived from sources other than seaweed have been identified as having enteric methane mitigation potential, these mitigants are outside the scope of this article.
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http://dx.doi.org/10.3389/fvets.2020.597430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785520PMC
December 2020

Prion protein post-translational modifications modulate heparan sulfate binding and limit aggregate size in prion disease.

Neurobiol Dis 2020 08 24;142:104955. Epub 2020 May 24.

Department of Pathology, Microbiology, and Immunology, UC Davis, Davis, CA 95616, USA; Departments of Medicine, UC San Diego, La Jolla, CA 92093, USA. Electronic address:

Many aggregation-prone proteins linked to neurodegenerative disease are post-translationally modified during their biogenesis. In vivo pathogenesis studies have suggested that the presence of post-translational modifications can shift the aggregate assembly pathway and profoundly alter the disease phenotype. In prion disease, the N-linked glycans and GPI-anchor on the prion protein (PrP) impair fibril assembly. However, the relevance of the two glycans to aggregate structure and disease progression remains unclear. Here we show that prion-infected knockin mice expressing an additional PrP glycan (tri-glycosylated PrP) develop new plaque-like deposits on neuronal cell membranes, along the subarachnoid space, and periventricularly, suggestive of high prion mobility and transit through the interstitial fluid. These plaque-like deposits were largely non-congophilic and composed of full length, uncleaved PrP, indicating retention of the glycophosphatidylinositol (GPI) anchor. Prion aggregates sedimented in low density fractions following ultracentrifugation, consistent with oligomers, and bound low levels of heparan sulfate (HS) similar to other predominantly GPI-anchored prions. Collectively, these results suggest that highly glycosylated PrP primarily converts as a GPI-anchored glycoform, with low involvement of HS co-factors, limiting PrP assembly mainly to oligomers. Since PrP is highly glycosylated, these findings may explain the high frequency of diffuse, synaptic, and plaque-like deposits in the brain as well as the rapid conversion commonly observed in human and animal prion disease.
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http://dx.doi.org/10.1016/j.nbd.2020.104955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425694PMC
August 2020

Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease.

J Clin Invest 2020 03;130(3):1350-1362

Department of Pathology, UCSD, La Jolla, California, USA.

Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp180Q/196Q), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease. Prnp180Q/196Q mice challenged with 2 subfibrillar, non-plaque-forming prion strains instead developed plaques highly enriched in ADAM10-cleaved PrP and heparan sulfate (HS). Intriguingly, a third strain composed of intact, glycophosphatidylinositol-anchored (GPI-anchored) PrP was relatively unchanged, forming diffuse, HS-deficient deposits in both the Prnp180Q/196Q and WT mice, underscoring the pivotal role of the GPI-anchor in driving the aggregate conformation and disease phenotype. Finally, knockin mice expressing triglycosylated PrP (Prnp187N) challenged with a plaque-forming prion strain showed a phenotype reversal, with a striking disease acceleration and switch from plaques to predominantly diffuse, subfibrillar deposits. Our findings suggest that the dominance of subfibrillar aggregates in prion disease is due to the replication of GPI-anchored prions, with fibrillar plaques forming from poorly glycosylated, GPI-anchorless prions that interact with extracellular HS. These studies provide insight into how PTMs impact PrP interactions with polyanionic cofactors, and highlight PTMs as a major force driving the prion disease phenotype.
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http://dx.doi.org/10.1172/JCI131564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269597PMC
March 2020

Generation of novel neuroinvasive prions following intravenous challenge.

Brain Pathol 2018 11 5;28(6):999-1011. Epub 2018 Jul 5.

Departments of Pathology and Medicine, UC San Diego, La Jolla, CA.

Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.
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http://dx.doi.org/10.1111/bpa.12598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123309PMC
November 2018

Asparagine and glutamine ladders promote cross-species prion conversion.

J Biol Chem 2017 11 20;292(46):19076-19086. Epub 2017 Sep 20.

From the Departments of Pathology and Medicine, University of California at San Diego, La Jolla, California 92093,

Prion transmission between species is governed in part by primary sequence similarity between the infectious prion aggregate, PrP, and the cellular prion protein of the host, PrP A puzzling feature of prion formation is that certain PrP sequences, such as that of bank vole, can be converted by a remarkably broad array of different mammalian prions, whereas others, such as rabbit, show robust resistance to cross-species prion conversion. To examine the structural determinants that confer susceptibility or resistance to prion conversion, we systematically tested over 40 PrP variants of susceptible and resistant PrP sequences in a prion conversion assay. Five key residue positions markedly impacted prion conversion, four of which were in steric zipper segments where side chains from amino acids tightly interdigitate in a dry interface. Strikingly, all five residue substitutions modulating prion conversion involved the gain or loss of an asparagine or glutamine residue. For two of the four positions, Asn and Gln residues were not interchangeable, revealing a strict requirement for either an Asn or Gln residue. Bank voles have a high number of Asn and Gln residues and a high Asn:Gln ratio. These findings suggest that a high number of Asn and Gln residues at specific positions may stabilize β-sheets and lower the energy barrier for cross-species prion transmission, potentially because of hydrogen bond networks from side chain amides forming extended Asn/Gln ladders. These data also suggest that multiple PrP segments containing Asn/Gln residues may act in concert along a replicative interface to promote prion conversion.
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http://dx.doi.org/10.1074/jbc.M117.794107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704488PMC
November 2017

Enhanced neuroinvasion by smaller, soluble prions.

Acta Neuropathol Commun 2017 04 21;5(1):32. Epub 2017 Apr 21.

Departments of Pathology and Medicine, UC San Diego, La Jolla, CA, USA.

Infectious prion aggregates can propagate from extraneural sites into the brain with remarkable efficiency, likely transported via peripheral nerves. Yet not all prions spread into the brain, and the physical properties of a prion that is capable of transit within neurons remain unclear. We hypothesized that small, diffusible aggregates spread into the CNS via peripheral nerves. Here we used a structurally diverse panel of prion strains to analyze how the prion conformation impacts transit into the brain. Two prion strains form fibrils visible ultrastructurally in the brain in situ, whereas three strains form diffuse, subfibrillar prion deposits and no visible fibrils. The subfibrillar strains had significantly higher levels of soluble prion aggregates than the fibrillar strains. Primary neurons internalized both the subfibrillar and fibril-forming prion strains by macropinocytosis, and both strain types were transported from the axon terminal to the cell body in vitro. However in mice, only the predominantly soluble, subfibrillar prions, and not the fibrillar prions, were efficiently transported from the tongue to the brain. Sonicating a fibrillar prion strain increased the solubility and enabled prions to spread into the brain in mice, as evident by a 40% increase in the attack rate, indicating that an increase in smaller particles enhances prion neuroinvasion. Our data suggest that the small, highly soluble prion particles have a higher capacity for transport via nerves. These findings help explain how prions that predominantly assemble into subfibrillar states can more effectively traverse into and out of the CNS, and suggest that promoting fibril assembly may slow the neuron-to-neuron spread of protein aggregates.
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http://dx.doi.org/10.1186/s40478-017-0430-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399838PMC
April 2017

Cross-species transmission of CWD prions.

Prion 2016 ;10(1):83-91

a Departments of Pathology and Medicine , UC San Diego , La Jolla , CA , USA.

Prions cause fatal neurodegenerative diseases in humans and animals and can be transmitted zoonotically. Chronic wasting disease (CWD) is a highly transmissible prion disease of wild deer and elk that affects cervids over extensive regions of the United States and Canada. The risk of cross-species CWD transmission has been experimentally evaluated in a wide array of mammals, including non-human primates and mouse models expressing human cellular prion protein. Here we review the determinants of cross-species CWD transmission, and propose a model that may explain a structural barrier for CWD transmission to humans.
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http://dx.doi.org/10.1080/19336896.2015.1118603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981193PMC
January 2017

Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death.

Am J Pathol 2015 Jul 5;185(7):1800-8. Epub 2015 May 5.

Department of Pathology, University of California-San Diego, La Jolla, California. Electronic address:

Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological insults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review discusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection.
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http://dx.doi.org/10.1016/j.ajpath.2015.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484218PMC
July 2015

Human prion protein sequence elements impede cross-species chronic wasting disease transmission.

J Clin Invest 2015 Apr 23;125(4):1485-96. Epub 2015 Feb 23.

Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the β2-α2 loop (residues 165-175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a β2-α2 loop (residues 165-175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross-species prion transmission.
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http://dx.doi.org/10.1172/JCI79408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396485PMC
April 2015

A proposed mechanism for the promotion of prion conversion involving a strictly conserved tyrosine residue in the β2-α2 loop of PrPC.

J Biol Chem 2014 Apr 4;289(15):10660-10667. Epub 2014 Mar 4.

Department of Pathology and Medicine, University of California San Diego, La Jolla, California 92093; Department of Pathology, Immunology, and Microbiology, University of California, Davis, California 95616. Electronic address:

The transmission of infectious prions into different host species requires compatible prion protein (PrP) primary structures, and even one heterologous residue at a pivotal position can block prion infection. Mapping the key amino acid positions that govern cross-species prion conversion has not yet been possible, although certain residue positions have been identified as restrictive, including residues in the β2-α2 loop region of PrP. To further define how β2-α2 residues impact conversion, we investigated residue substitutions in PrP(C) using an in vitro prion conversion assay. Within the β2-α2 loop, a tyrosine residue at position 169 is strictly conserved among mammals, and transgenic mice expressing mouse PrP having the Y169G, S170N, and N174T substitutions resist prion infection. To better understand the structural requirements of specific residues for conversion initiated by mouse prions, we substituted a diverse array of amino acids at position 169 of PrP. We found that the substitution of glycine, leucine, or glutamine at position 169 reduced conversion by ∼ 75%. In contrast, replacing tyrosine 169 with either of the bulky, aromatic residues, phenylalanine or tryptophan, supported efficient prion conversion. We propose a model based on a requirement for tightly interdigitating complementary amino acid side chains within specific domains of adjacent PrP molecules, known as "steric zippers," to explain these results. Collectively, these studies suggest that an aromatic residue at position 169 supports efficient prion conversion.
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http://dx.doi.org/10.1074/jbc.M114.549030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036184PMC
April 2014

Prion transmission prevented by modifying the β2-α2 loop structure of host PrPC.

J Neurosci 2014 Jan;34(3):1022-7

Departments of Pathology and Medicine, University of California, San Diego, La Jolla, California 92093, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain, Institut für Molekularbiologie und Biophysik, ETH Zürich, CH-8093 Zürich, Switzerland, Institute of Laboratory Animal Science and Biomodels, University of Veterinary Medicine, 1210 Vienna, Austria, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain, Department of Integrated Structural and Computational Biology, and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California 92037, UniversitätsSpital Zürich, Institute of Neuropathology, CH-8091 Zürich, Switzerland, and Department of Pathology, Immunology, and Microbiology, University of California, Davis, California 95616.

Zoonotic prion transmission was reported after the bovine spongiform encephalopathy (BSE) epidemic, when >200 cases of prion disease in humans were diagnosed as variant Creutzfeldt-Jakob disease. Assessing the risk of cross-species prion transmission remains challenging. We and others have studied how specific amino acid residue differences between species impact prion conversion and have found that the β2-α2 loop region of the mouse prion protein (residues 165-175) markedly influences infection by sheep scrapie, BSE, mouse-adapted scrapie, deer chronic wasting disease, and hamster-adapted scrapie prions. The tyrosine residue at position 169 is strictly conserved among mammals and an aromatic side chain in this position is essential to maintain a 310-helical turn in the β2-α2 loop. Here we examined the impact of the Y169G substitution together with the previously described S170N, N174T "rigid loop" substitutions on cross-species prion transmission in vivo and in vitro. We found that transgenic mice expressing mouse PrP containing the triple-amino acid substitution completely resisted infection with two strains of mouse prions and with deer chronic wasting disease prions. These studies indicate that Y169 is important for prion formation, and they provide a strong indication that variation of the β2-α2 loop structure can modulate interspecies prion transmission.
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http://dx.doi.org/10.1523/JNEUROSCI.4636-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891945PMC
January 2014

Structure of the β2-α2 loop and interspecies prion transmission.

FASEB J 2012 Jul 9;26(7):2868-76. Epub 2012 Apr 9.

Department of Pathology, University of California, San Diego, La Jolla, California, USA.

Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The β2-α2 loop region of endogenous prion protein, PrP(C), has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar β2-α2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the β2-α2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered β2-α2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrP(C) from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.
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http://dx.doi.org/10.1096/fj.11-200923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382101PMC
July 2012

Alteration of the chronic wasting disease species barrier by in vitro prion amplification.

J Virol 2011 Sep 22;85(17):8528-37. Epub 2011 Jun 22.

Department of Microbiology, Immunology and Pathology, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523-1619, USA.

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids now detected in 19 states of the United States, three Canadian provinces, and South Korea. Whether noncervid species can be infected by CWD and thereby serve as reservoirs for the infection is not known. To investigate this issue, we previously used serial protein misfolding cyclic amplification (sPMCA) to demonstrate that CWD prions can amplify in brain homogenates from several species sympatric with cervids, including prairie voles (Microtus ochrogaster) and field mice (Peromyscus spp.). Here, we show that prairie voles are susceptible to mule deer CWD prions in vivo and that sPMCA amplification of CWD prions in vole brain enhances the infectivity of CWD for this species. Prairie voles inoculated with sPMCA products developed clinical signs of TSE disease approximately 300 days prior to, and more consistently than, those inoculated with CWD prions from deer brain. Moreover, the deposition patterns and biochemical properties of protease-resistant form of PrP (PrP(RES)) in the brains of affected voles differed from those in cervidized transgenic (CerPrP) mice infected with CWD. In addition, voles inoculated orally with sPMCA products developed clinical signs of TSE and were positive for PrP(RES) deposition, whereas those inoculated orally with deer-origin CWD prions did not. These results demonstrate that transspecies sPMCA of CWD prions can enhance the infectivity and adapt the host range of CWD prions and thereby may be useful to assess determinants of prion species barriers.
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http://dx.doi.org/10.1128/JVI.00809-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165824PMC
September 2011

Trans-species amplification of PrP(CWD) and correlation with rigid loop 170N.

Virology 2009 Apr 9;387(1):235-43. Epub 2009 Mar 9.

Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523, USA.

Chronic wasting disease (CWD) is an efficiently transmitted spongiform encephalopathy of cervids. Whether CWD could represent a threat to non-cervid species remains speculative. Here we show that brain homogenates from several CWD-susceptible non-cervid species, such as ferrets and hamsters, support amplification of PrP(CWD) by sPMCA, whereas brain homogenates from CWD-resistant species, such as laboratory mice and transgenic mice expressing human PrP(C) [Tg(HuPrP) mice], do not. We also investigated whether several North American species that share the environment with cervids would support amplification of PrP(CWD) by sPMCA. Three native rodent species, including voles and field mice, supported PrP(CWD) amplification, whereas other species (e.g. prairie dog, coyote) did not. Analysis of PrP sequences suggests that an ability to support amplification of PrP(CWD) in trans-species sPMCA is correlated with the presence of asparagine at position 170 of the substrate species PrP. Serial PMCA may offer insights into species barriers to transmission of CWD.
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http://dx.doi.org/10.1016/j.virol.2009.02.025DOI Listing
April 2009

Efficient in vitro amplification of chronic wasting disease PrPRES.

J Virol 2007 Sep 6;81(17):9605-8. Epub 2007 Jun 6.

Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.

Chronic wasting disease (CWD) of cervids is associated with conversion of the normal cervid prion protein, PrP(C), to a protease-resistant conformer, PrP(CWD). Here we report the use of both nondenaturing amplification and protein-misfolding cyclic amplification (PMCA) to amplify PrP(CWD) in vitro. Normal brains from deer, transgenic mice expressing cervid PrP(C) [Tg(cerPrP)1536 mice], and ferrets supported amplification. PMCA using normal Tg(cerPrP)1536 brains as the PrP(C) substrate produced >6.5 x 10(9)-fold amplification after six rounds. Highly efficient in vitro amplification of PrP(CWD) is a significant step toward detection of PrP(CWD) in the body fluids or excreta of CWD-susceptible species.
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http://dx.doi.org/10.1128/JVI.00635-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951436PMC
September 2007
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