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Published: 4 June 2021
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1

Premzl, Marko, and Premzl@anu edu au premzl@excite com Marko. "Prion Protein Gene and Its Shadow." The Australian National University. The John Curtin School of Medical Research, 2004. http://thesis.anu.edu.au./public/adt-ANU20050328.164529.

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Prion protein (PrP) is best known for its involvement in prion diseases. A normal, dynamic isoform of prion protein (PrP^C) transforms into a pathogenic, compact isoform (PrP^Sc) during prion disease pathogenesis. The PrP^Sc, acting as a template upon which PrP^C molecules are refolded into a likeness of itself, accumulates in the brain neurones and causes disease. It is the only known component of prions, proteinaceous infectious particles. Both prion protein isoforms have the same primary amino acid structure and are encoded by the same prion protein gene (PRNP). PRNP determines susceptibility/disposition to prion diseases and their phenotypes.¶The normal function of PRNP is elusive. The Prnp knock-out mice with disrupted ORF show only very subtle phenotype. A number of hypotheses were proposed on the function of mammalian PRNP. The extracellular, GPI-anchored, glycosylated mammalian PrP^C expressed in a heterogenous set of cells could: transport copper from extracellular to intracellular milieu, buffer copper from synapse, contribute to redox signalling, act neuroprotectively, mediate cell-cell contacts, affect lymphocyte activation, participate in nucleic acid metabolism, be a memory molecule, and be a signal-transduction protein.¶ Experimental evidence demonstrated a redundancy between the PRNP and another, unknown gene. The critical issue therefore is to discover new genes homologous with PRNP, candidates for this redundancy. Using unpublished data, a sequence of zebrafish cDNA sequenced by Prof. Tatjana Simonic’s group (University of Milan, Italy), I discovered a new paralogue of PRNP. By searching manually, and in a targeted fashion, data deposited in public biological databases, I compiled support for the new human gene Shadow of prion protein (SPRN) including the direct evidence, homology-based evidence and ab initio gene prediction. The protein product called Shadoo (shadow in Japanese) is an extracellular, potentially glycosylated and GPI-anchored protein of a mature size of 100-odd amino acids. It is conserved from fish (zebrafish, Fugu, Tetraodon) to mammals (human, mouse, rat), and exhibits similarity of overall protein features with PrP. Most remarkably, the Sho is the first human/mammalian protein apart from PrP that contains the middle hydrophobic region that is essential for both normal and pathogenic properties of PrP. As this region is critical for heterodimerization of PrP, Sho may have potential to interact with PrP and is a likely candidate for the Protein X. Mammalian SPRN could be predominantly expressed in brain (Tatjana Simonic Lab, University of Milan, Italy).¶ Using the same approach to search public databases, I found, in addition, a fish duplicate of SPRN called SPRNB, and defined a new vertebrate SPRN gene family. Further, I also expanded a number of known fish genes from the PRNP gene family. The total number of the new genes that I discovered is 11. With the representatives of two vertebrate gene family datasets in hand, I conducted comparative genomic analysis in order to determine evolutionary trajectories of the SPRN and PRNP genes. This analysis, complemented with phylogenetic studies (Dr. Lars Jermiin, University of Sydney, Australia), demonstrated conservative evolution of the mammalian SPRN gene, and more relaxed evolutionary constraints acting on the mammalian PRNP gene. This evolutionary dialectic challenges widely adopted view on the “highly conserved vertebrate” PRNP and indicates that the SPRN gene may have more prominent function. More conserved Sprn could therefore substitute for the loss of less conserved, dispensable Prnp in the Prnp knock-out mice. Furthermore, the pathogenic potential of PRNP may be a consequence of relaxed evolutionary constraints.¶ Depth of comparative genomic analysis, strategy to understand biological function, depends on the number of species in comparison and their relative evolutionary distance. To understand better evolution and function of mammalian PRNP, I isolated and characterized the PRNP gene from Australian model marsupial tammar wallaby (Macropus eugenii). Marsupials are mammals separated from their eutherian relatives by roughly 180 million years. Comparison of the tammar wallaby and Brazilian opossum PrP with other vertebrate PrPs indicated patterns of evolution of the PrP regions. Whereas the repeat region is conserved within lineages but differs between lineages, the hydrophobic region is invariably conserved in all the PrPs. Conservation of PrP between marsupials and eutherians suggests that marsupial PrP could have the same pathogenic potential as eutherian PrPs. Using the marsupial PRNP gene in comparison with the PRNP genes from eutherian species in which prion diseases occur naturally (human, bovine, ovine) or experimentally (mouse), I defined gene regions that are conserved mammalian-wide and showed the utility of the marsupial genomic sequence for cross-species comparisons. These regions are potential regulatory elements that could govern gene expression and posttranscriptional control of mRNA activity. These findings shed new light on the normal function of mammalian PRNP supporting best the signal-transduction hypothesis. The normal function of PRNP may be triggering of signalling cascades which contribute to cell-cell interactions and may act anti-apoptotically. Yet, in the heterogenous set of cells expressing PrP^C these pathways will contribute to a number of cell-specific phenotypes, such as the synaptic plasticity and activation of lymphoid cells.
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2

Sun, Meng. "Development of the new yeast-based assays for prion properties." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/45831.

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Prion is an infectious isoform of a normal cellular protein which is capable of converting the non-prion form of the same protein into the alternative prion form. Mammalian prion protein PrP is responsible for prion formation in mammals, causing a series of fatal and incurable prion diseases. (1) We constructed, for the first time, a two-component system to phenotypically monitor the conformational status of PrP in the yeast cells. In this system, the prion domain of Sup35 (Sup35N) was fused to PrP90-230, and the initial formation of the PrPSc-like conformation stimulated prion formation of Sup35N, which in turn converted soluble Sup35 into the prion isoform, leading to a detectable phenotype. Prion-like properties of PrP were studied in this novel yeast model system. Additionally, we employed this system to study amyloidogenic protein Aβ42 aggregation in the yeast model. It has been suggested that the ability to form transmissible amyloids (prions) is widespread among yeast proteins and is likely intrinsic to proteins from other organisms. However, the distribution of yeast prions in natural conditions is not yet clear, which prevents us from understanding the relationship between prions and their adaptive roles in various environmental conditions. (2) We modified and developed sequence and phenotype-independent approaches for prion detection and monitoring. We employed these approaches for prion-profiling among yeast strains of various origins. (3) Lastly, we found a prion-like state [MCS+] causing nonsense suppression in the absence of the Sup35 prion domain. Our results suggested that [MCS+] is determined by both a prion factor and a nuclear factor. The prion-related properties of [MCS+] were studied by genetic and biochemical approaches.
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3

Apetri, Constantin Adrian. "Folding of the Prion Protein." Case Western Reserve University School of Graduate Studies / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=case1080747299.

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4

Saijo, Eri. "INVESTIGATING THE ROLE OF PRION PROTEIN POLYMORPHISMS ON PRION PATHOGENESIS." UKnowledge, 2012. http://uknowledge.uky.edu/microbio_etds/4.

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Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are lethal and infectious neurodegenerative diseases of humans and animals. The misfolding of the normal, or cellular isoform of the prion protein (PrPC) into the abnormal disease-associated isoform of PrP (PrPSc) could change the properties of PrP, consequently, PrPSc has lethal infectivity to transmit diseases. The proteinaceous infectious particle consisting mainly of PrPSc is called prion. Transmissibility of prions is strongly influenced by multiple factors including PrP polymorphisms, species barriers (PrP sequence specificity) and prion strains (conformational specificity) by unknown mechanisms. Even though the ability of prions to cross a species barrier has been recognized, the precise mechanisms of interspecies prion transmission remain unclear. This dissertation research was conducted in order to learn more about the molecular mechanisms of conversion, propagation and transmission of PrPSc; about determinants of genetic susceptibility to infection in prion diseases; and about understanding those mechanisms, which might govern the zoonotic potential of prion diseases. First, we investigated the transmissibility risk of multiple strains of Chronic Wasting Disease, which is a cervid TSE, with humanized transgenic mice and showed that the transmission barriers between cervid and the humanized mice are high. Next, the structural factors underlying the species barrier of prion diseases were studied using cell culture systems by systematically introducing amino acid substitutions in the regions of PrP, where the most divergences of different PrP species are recognized. Thirdly, we investigated the effects of the genetic susceptibility to prions as well as conversion kinetics and properties of PrPSc using Tg mice expressing ovine PrP polymorphism (OvPrP) at codon 136 either alanine (A) or valine (V). The templating characteristics of OvPrPSc-V136 were dominant over OvPrPSc-A136 under co-expressions of OvPrPC-A136 and OvPrPC-V136. Finally, the function of PrP was studied in relation to the pathogenesis of Alzheimer’s disease. These studies demonstrated that the conformational compatibility between PrPC and PrPSc contributed to the conversion kinetics and species barrier. We concluded that the conformational compatibility of PrPC to PrPSc is controlled not only by the PrP sequence specificity but also by the tertiary structure of PrPC.
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5

Resenberger, Ulrike. "Das zelluläre Prion-Protein als Mediator der Scrapie-Prion-Protein- und Amyloid Beta-induzierten Neurotoxizität." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-153987.

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6

Papadopoulos, Maria. "The prion protein interacts with Bcl-2 and Bax proteins." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0026/MQ50849.pdf.

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7

Hart, Tanya Clare. "Mutational studies of prion protein folding." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418318.

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8

Davies, Paul. "The metallochemistry of the prion protein." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512372.

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The Prion protein (PrP) is a cell surface glycoprotein that has been directly implicated in the pathogenesis of a range of neurological disorders referred to as the transmissible spongiform encephalopathies (TSE’s). The protein has been shown to bind copper within its unstructured N-terminus but the affinity and stoichiometry of the association is a matter of some debate. In addition, the functional significance of this copper binding has yet to be elucidated. This study aimed to determine accurate metal binding parameters for PrP through the use of calorimetry and to provide insight into the potential redox implications of metal once bound. A method of analysis for complex binding to proteins is thoroughly assessed and found to be suitable. The study also aimed to qualify the involvement of metals in the proteins remarkable ability to survive in the environment. This study confirms that PrP binds copper with an affinity relative to the amount of copper available to the protein. A high nanomolar affinity is reported within two regions on the protein, the octarepeat and the 5th site. Binding within the octarepeat region is found to be highest at low copper concentrations, reducing to micromolar affinity when copper levels exceed equivalents of 1. There is also strong evidence of a complex and cooperative binding mechanism. The 5th site also displays high nanomolar affinity for a single atom of copper. These two regions on the protein also interact in the coordination of copper (II). The copper bound protein is highly redox active and is capable of fully reversible cycling of electrons that are dependent mainly on the octarepeat. The protein does bind other divalent cations but none appear to be physiologically relevant considering the amount of these free metal ions in the body. When adsorbed to model clays, PrP is able to survive for long periods at room temperature. This longevity is increased significantly by the presence of metals in the soil, especially manganese. These data provide confirmation of the precise parameters of divalent cation binding to PrP. It also confirms that the copper bound protein is capable of a physiological redox role.
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9

Steele, Andrew D. Ph D. Massachusetts Institute of Technology. "Prion protein in health and disease." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/42396.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008.
Includes bibliographical references.
The prion protein (PrP) is a conserved glycoprotein tethered to cell membranes by a glycosylphosphatidylinositol anchor. In mammals, PrP is expressed in many tissues, most abundantly in brain, heart, and muscle. Importantly, PrP is required for prion diseases, which are neurodegenerative diseases associated with misfolding and aggregation of PrP. PrP can adopt a self-perpetuating conformation that templates the misfolding of normal PrP molecules into its pathogenic conformation, termed PrPsC. The role of PrPSC in the pathogenesis of prion diseases, or transmissible spongiform encephalopathies, has been studied intensively yet the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Much less attention has been focused on the role of PrP in normal physiology despite the possibility that deciphering PrP's normal function could help to understand prion diseases. My thesis work has spanned both the study of the normal function of PrP and the neurotoxic pathways that are involved in prion pathogenesis. Because prion disease and other neurodegenerative diseases share protein misfolding as the primary etiology, I aimed to determine whether PrP contributed to other neurodegenerative diseases apart from prion diseases. We deleted PrP from several well established transgenic mouse models of neurodegenerative disease, including Tauopathy, Parkinson's and Huntington's diseases. Deleting PrP did not substantially alter the disease phenotypes of the models that we tested, suggesting that PrP is not a major contributor to or protector against these disorders. In addition, in collaborative efforts we determined that PrP knockout mice have defects in hematopoiesis and neurogenesis.
(cont.) Hematopoietic stem cells from PrP knockout mice have defects in self-renewal, as manifested during serial bone marrow transplantation or during the aging process. PrP knockout mice also display a slight reduction in cellular proliferation and/or neurogenesis in the adult brain. I also participated in the development of a video based behavior recognition system. We used this system to quantify the home cage behavioral changes in two mouse models of neurodegeneration, Huntington's disease and prion disease. Because studies of prion disease have been focused primary on the pathological level, I have attempted to elucidate the molecular pathways responsible for mediating neurotoxicity in a mouse model of infectious prion disease. In the first series of studies we tested whether apoptotoic cell death pathways are activated in prion disease. We inoculated mice deficient for Caspase-12 and Bax, both of which have been implicated in mediating prion toxicity, but did not observe any protection against disease in these mice. Also, neuronal overexpression of Bcl-2 did not protect against prion toxicity and instead, inhibition of apoptosis may have enhanced several aspects of disease (as did deletion of Bax). In a second attempt at determining pathways involved in prion toxicity, I determined that deletion of heat shock factor 1 (Hsfl), a stress responsive transcription factor, protects against prion toxicity. Mice that are deficient for Hsfl succumb to prion disease faster than controls, despite similar pathological and behavioral onset.
by Andrew D. Steele.
Ph.D.
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10

Young, Duncan Scott. "Post-translational modifications of prion protein." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615154.

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11

Apodaca, Jennifer J. "Regulation of prion protein in yeast and mammalian cells via ubiquitin mediated degradation a dissertation /." San Antonio : UTHSC, 2008. http://proquest.umi.com.libproxy.uthscsa.edu/pqdweb?did=1594496391&sid=6&Fmt=2&clientId=70986&RQT=309&VName=PQD.

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12

Bruns, Christopher. "Characterization of interactors of the cellular prion protein." kostenfrei, 2010. https://mediatum2.ub.tum.de/node?id=829427.

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13

Hashem, Dabaghian Alireza. "Functional knockout of cellular prion protein in mouse neuroblastoma cell cultures by overexpression of anti-prion protein intrabodies." [S.l. : s.n.], 2002. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB10073766.

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14

Mead, Simon Harvey. "Molecular genetic analysis of the prion protein gene locus in human prion disease." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417947.

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15

Krejciova, Zuzana. "Exposure and response of human non-neuronal cells to prions in vitro." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/8186.

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Despite intensive research, the cellular and molecular mechanisms involved in human cellular susceptibility to prion infection remain poorly defined, in part due to the continuing lack of cultured human cells that are susceptible to infection with human prions. Such culture models would present distinct advantages including speed and expense compared with animal models, and would provide systems in which to investigate the interaction between PrPC and PrPSc, the basis of cellular susceptibility, the nature of the species barrier and the mechanism of prion propagation in situ. This study sought to examine whether non-neuronal cells might provide opportunities to establish human cell lines replicating human prions. A human follicular dendritic cell-like cell line (termed HK) was obtained, further characterised and then tested for its ability to support human prion replication. The mechanisms of internalisation, intracellular trafficking and the eventual fate of exogenous PrPSc taken up by these cells were also examined. This thesis similarly examined the cellular response of human embryonic stem cells (hESC) to acute exposure to human and animal prions. PrPC was found to be abundantly expressed by HK cells and HK cell extracts were found to support conversion to PrPSc in a cell-free conversion assay. However, HK cells exposed to infectious brain homogenates failed to accumulate PrPSc or become infected in vitro. Exposed HK and hESC did display a readily detectable, time dependent uptake of PrPSc from medium spiked with prion-infected brain homogenates that was independent of the species, disease phenotype and PRNP codon 129 genotype of the human source and the recipient cells. The exposed cells showed intensely labelled intracellular accumulations of PrPSc with coarse granular morphology, largely in the juxtanuclear region of cytoplasm. However, when the brain-spiked medium was withdrawn and cells were given control medium, the intensity and extent of PrPSc immunostaining rapidly diminished. Co-localisation studies implicated caveolae-mediated endocytic uptake of exogenous PrPSc, apparently preceding uptake via clathrin coated pits in HK cells. Evidence suggesting that the endosomal recycling compartment and lysosomes are involved in intracellular trafficking and degradation of exogenous PrPSc was also found. Understanding the cell biology of these processes may help to explain why the majority of cultured cells are refractory to prion infection in vitro. Internalization of misfolded PrP and its subsequent degradation in the lysosomal compartment might function as a self-protective cellular mechanism, serving to eliminate non-native, presumably dysfunctional and potentially dangerous PrP conformers, whether generated endogenously or acquired through exposure to exogenous prion infectivity.
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16

Hundt, Christoph. "Interaction studies of the cellular prion protein." Diss., lmu, 2002. http://edoc.ub.uni-muenchen.de/218/.

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17

Eaglestone, Simon Spencer. "Studies of Sup35p : a yeast prion protein." Thesis, University of Kent, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297347.

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18

Wightman, Lionel. "Linear epitope tagging of the prion protein." Thesis, University of Reading, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282977.

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19

Shamsir, Omar Mohd Shahir. "Molecular dynamics studies of human prion protein." Thesis, University of Exeter, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418486.

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20

Ford, Melanie. "Cellular prion protein expression in the mouse." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249698.

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21

Alibhai, James David. "Role of misfolded prion protein in neurodegeneration." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15851.

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Chronic neurodegenerative diseases, such as Alzheimer’s disease, prion diseases and many others are unified by the aberrant folding of a host encoded protein to a disease-associated isoform and the predictable cell-to-cell spread of disease-associated misfolded proteins via a putative prion-like mechanism. Prion diseases, for example, are associated with the aberrant folding of host encoded prion protein (PrPC) to a disease-associated isoform, which acts as a seed for the further conversion of PrPC to misfolded protein species. The role of misfolded prion protein in neurodegeneration remains unclear. Accumulation and spread of misfolded prion protein is typically slow and progressive, correlating with neurodegeneration. A number of studies show that mice are susceptible to prion disease with characteristic hallmarks of prion pathology but in the presence of little detectable misfolded prion protein (e.g. the GSS/101LL model). In this thesis I test the hypothesis that detectable species of misfolded prion protein correlate with neurodegeneration and spreads in a predictable, progressive fashion from one anatomically distinct brain region to the next. Using the GSS/101LL model, misfolded prion protein was detected as mostly PK-sensitive isoforms (PrPsen). The progression and pathological presentation is comparable to other prion diseases with larger quantities of PK resistant prion isoforms. A highly sensitive in vitro assay system (the QuIC assay) was subsequently used to establish the extent that misfolded protein was present within the brain. Amyloidogenic prion seeds were found to be widespread throughout the brain from an early stage and spread rapidly throughout the brain. Absence of neurodegeneration in certain brain regions is not due to differing quantities of prion seeds between regions or time exposed to prion seeds, as unaffected regions are exposed to comparative quantities of prion seeds for the same time-period as regions of the brain which eventually succumb to neurodegeneration. These results indicate a clear dissociation between prion seeds and neurotoxicity. They highlight the need to understand regional host responses to prion seeds that may evoke neurodegeneration in some but resilience in others. To test this, transcriptomic analysis was carried out on brain samples from regions undergoing neurodegeneration and unaffected regions. A gene profile signature of hybrid pro-and anti-inflammatory response was observed in regions undergoing neurodegeneration. However, large cohorts of genes were down-regulated across all regions tested, including pro-inflammatory genes and a large proportion of genes involved within transcriptional and translational regulation and function. These results highlight the possible molecular pathways in response to the presence of misfolded protein. In summary, misfolded prion protein accumulates rapidly across the CNS but only specific brain regions undergo neurodegeneration. In the presence of the misfolded protein, the host elicits a robust molecular response. The additional activation of glial cells within regions undergoing neurodegeneration highlights their importance in disease. It is therefore proposed that misfolded prion protein, alone, is not sufficient to trigger neurodegeneration. This gives rise to a “multi-hit” hypothesis whereby two or more factors, for example the accumulation of misfolded protein and glial cell response, are required to trigger neurodegeneration.
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Bunn, Tristan. "Prion protein biochemistry in Creutzfeldt-Jakob disease." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/23281.

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23

Hashem, Dabaghian Alireza. "Functional knockout of cellular prion protein in mouse neuroblastoma cell cultures by over-expression of anti-prion protein intrabodies." [S.l. : s.n.], 2002. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB10252173.

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24

Sanghera, Narinder. "The interaction of the prion protein with lipid membranes and implications for prion conversion." Thesis, University of Warwick, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247140.

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25

Mashima, Tsukasa. "The structural analysis of RNA aptamer against prion protein and its anti-prion activity." Kyoto University, 2013. http://hdl.handle.net/2433/170071.

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Nitschke, Cindy. "Humorale und zelluläre Immunantwort gegen das Prion-Protein." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=980934567.

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27

Sattar, Zahid. "Breaking immune tolerance to prion protein in mice." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406867.

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Borumand, Maryam. "Interaction of prion protein with plasminogen activation system." Thesis, University of East Anglia, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439929.

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Taylor, David Richard. "Mechanisms of endocytosis of the cellular prion protein." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434253.

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Kirby, Louise. "In vitro conversion studies of the prion protein." Thesis, University of Reading, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408319.

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Starke, Richard David. "The expression of prion protein in the vasculature." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406693.

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32

Kocisko, David A. (David Allan). "Cell-free formation of protease-resistant prion protein." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/42578.

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33

Come, Jon H. (Jon Harold). "Models for protein assembly in the prion diseases." Thesis, Massachusetts Institute of Technology, 1994. http://hdl.handle.net/1721.1/17371.

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34

Schiff, Edwin. "Intra- and intercellular trafficking of the prion protein." Paris 6, 2007. http://www.theses.fr/2007PA066510.

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La majorité des patients affectés par des ESST (encéphalopathie subaiguës spongiformes transmissibles) héréditaires sont hétérozygotes, exprimant alors une version saine de la protéine prion et une version mutée dans leurs cellules. J’ai reproduit cette situation in vitro en co-exprimant un plasmide codant pour une protéine sauvage avec des plasmides codants pour différentes versions mutées. Nos expériences suggèrent une interaction et colocalisation dans l’appareil Golgi et sur la membrane plasmique dans des lipid rafts. Dans la deuxième partie, je me suis intéressé à la question de la dissémination des prions entres les cellules et particulièrement à leur envahissement du système périphérique neuronal. Les «TNTs» (tunneling nanotubes) ont récemment été décrits comme des tubes membranaires fins, dont les cellules se servent pour la communication intercellulaire. Dans cette partie je montre que les prions exploitent les TNTs pour leur dissémination intercellulaire.
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35

Haigh, Cathryn Louise. "Regulation of prion protein expression and cellular activity." Thesis, University of Bath, 2006. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423484.

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36

Hatcher, Kristen-Louise. "Conformation Based Reagents for the Detection of Disease-Associated Prion Protein." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1232747817.

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37

Biggi, Silvia. "Tackling Prion Replication and Toxicity by Targeting the Cellular Prion Protein with Different Pharmacological Strategies." Doctoral thesis, Università degli studi di Trento, 2019. http://hdl.handle.net/11572/246789.

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The great majority of therapeutic strategies tested so far for prion diseases, fatal transmissible neurodegenerative disorders, tackled PrPSc, the infectious isoform of the cellular prion protein (PrPC), with largely unsuccessful results. Conversely, targeting PrPC is a poorly explored strategy. In this thesis, I exploited the concepts of altering PrPC cell surface localization and tackling PrPC-mediated cytotoxicity to design two different screening paradigms and study the effect of novel anti-prion compounds. We recently shed light on the mode of action of chlorpromazine, an anti-psychotic drug known to inhibit prion replication and toxicity by inducing the re-localization of PrPC from the plasma membrane. Unfortunately, chlorpromazine possesses pharmacokinetic properties unsuitable for chronic use in vivo, namely low specificity and high toxicity. In the first part of my thesis, I employed cells expressing EGFP-PrP to carry out a semi-automated high content screening (HCS) of a chemical library directed at identifying non-cytotoxic molecules capable of specifically re-localizing PrPC from the plasma membrane as well as inhibiting prion replication and toxicity in cell cultures. I found four candidate hits inducing a significant reduction in cell surface PrPC, one of which also inhibited prion propagation and toxicity in cell cultures in a strain-independent fashion. In a previous publication, an artificial mutant of PrPC (ΔCR), sensitizing cells to several cationic antibiotics as Zeocin, was used to screen a library of compounds rescuing Zeocin-induced cytotoxicity. However, the main hit of the screening, named LD24, had low efficiency and high toxicity. In the second part of my thesis, I coupled cycles of chemical rearrangement and screening steps using ΔCR cells, to test a small library of derivatives of LD24 and validated the selected compounds with a panel of cellular assays. I found that one molecule, SM231 and its derivative SM884, counteracted PrPC-mediated toxicity in cellular and ex vivo models of prion disease and Alzheimer's disease. Collectively, these studies define new screening methods and novel anti-prion compounds supporting the notion that removing PrPC from the cell surface and blocking its cytotoxicity could represent viable therapeutic strategies for prion diseases and other neurodegenerative conditions.
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38

Biggi, Silvia. "Tackling Prion Replication and Toxicity by Targeting the Cellular Prion Protein with Different Pharmacological Strategies." Doctoral thesis, Università degli studi di Trento, 2019. http://hdl.handle.net/11572/246789.

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The great majority of therapeutic strategies tested so far for prion diseases, fatal transmissible neurodegenerative disorders, tackled PrPSc, the infectious isoform of the cellular prion protein (PrPC), with largely unsuccessful results. Conversely, targeting PrPC is a poorly explored strategy. In this thesis, I exploited the concepts of altering PrPC cell surface localization and tackling PrPC-mediated cytotoxicity to design two different screening paradigms and study the effect of novel anti-prion compounds. We recently shed light on the mode of action of chlorpromazine, an anti-psychotic drug known to inhibit prion replication and toxicity by inducing the re-localization of PrPC from the plasma membrane. Unfortunately, chlorpromazine possesses pharmacokinetic properties unsuitable for chronic use in vivo, namely low specificity and high toxicity. In the first part of my thesis, I employed cells expressing EGFP-PrP to carry out a semi-automated high content screening (HCS) of a chemical library directed at identifying non-cytotoxic molecules capable of specifically re-localizing PrPC from the plasma membrane as well as inhibiting prion replication and toxicity in cell cultures. I found four candidate hits inducing a significant reduction in cell surface PrPC, one of which also inhibited prion propagation and toxicity in cell cultures in a strain-independent fashion. In a previous publication, an artificial mutant of PrPC (ΔCR), sensitizing cells to several cationic antibiotics as Zeocin, was used to screen a library of compounds rescuing Zeocin-induced cytotoxicity. However, the main hit of the screening, named LD24, had low efficiency and high toxicity. In the second part of my thesis, I coupled cycles of chemical rearrangement and screening steps using ΔCR cells, to test a small library of derivatives of LD24 and validated the selected compounds with a panel of cellular assays. I found that one molecule, SM231 and its derivative SM884, counteracted PrPC-mediated toxicity in cellular and ex vivo models of prion disease and Alzheimer's disease. Collectively, these studies define new screening methods and novel anti-prion compounds supporting the notion that removing PrPC from the cell surface and blocking its cytotoxicity could represent viable therapeutic strategies for prion diseases and other neurodegenerative conditions.
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39

Doolan, Kyle M. "Engineering and characterization of protein-protein interactions in prion disease and therapy." Thesis, University of Delaware, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3730253.

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Prion diseases are caused by a structural rearrangement of the cellular prion protein, PrPC, into a disease-associated conformation, PrPSc, that is β-sheet rich and can form amyloid deposits in the brain. PrPSc formation induces neuronal death and an invariably fatal neurodegenerative disease. The pathology of prion diseases is among the best understood of a group of neurodegenerative diseases that show similar features including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease because it is experimentally infectious. Samples containing PrPSc when introduced into a host bind to native PrPC and promote conversion to PrPSc in a seeding or templating manner. In this work we seek an understanding of how particular amino acids contribute to prion disease pathogenesis and ultimately how this information can be translated to the production of more efficient therapies.

We developed a high-throughput screening method to determine the amino acid specific effects of the PrP sequence contributing to the interaction with anti-prion antibodies and alternative PrP conformations. A library of mouse PrP mutants expressed on the surface of yeast cells was screened for their binding interactions with anti-prion antibodies and beta-sheet rich PrP conformations. Those substitutions in PrP that prevented these interactions were identified by single molecule real-time (SMRT) sequencing of the screened population, providing greater than 10,000 full-length nucleotide sequences. The sequences were then aligned to the wild-type PrP gene to identify mutations. We found that optimization of the alignment scoring parameters for the Needleman-Wunsch algorithm and rejecting the lowest 10% of sequences in terms of sequence quality reduced the substitution error rate of sequencing from 7.90 x 10-5 to 2.19 x 10-5 and improves the statistical power of the method. By examining the entire gene sequences correlated to the protein function, we were able to obtain residue-level resolution of conformational protein-protein interaction interfaces that are critical for binding, as well as a quantitative measure of the impact of mutations on binding affinity.

When the library was screened against anti-prion antibodies we found that they made contacts with discontinuous residues that are brought into close proximity when PrP adopts an alpha-helix rich and PrPC like structure. When the library was screened against different conformations of PrP conformation specific interactions were observed. We found that antibodies ICSM18 and D18 binding was influenced by discontinuous residues in helix 1 of PrP, brought into close proximity to one another only when the alpha helix was intact, while full affinity of the 6H4 antibody was dependent on the negative charge on the genetically distal but conformationally adjacent D201 residue. Furthermore, the relative enrichment of mutants correlated to the magnitude of the change in binding affinity, demonstrating how residues such as W144 were essential for binding for all three antibodies, while residues such as D201 only modestly contributed to 6H4 affinity. We observed that high affinity PrP-PrP interactions with yeast surface displayed PrP were consistently achieved when unbound PrP was folded into beta-sheet rich structures. These interactions persisted over a wide range of solution conditions and blocking conditions, and were facilitated predominantly by residues 101-111, though other regions throughout the entire protein such as residues 28-33 and 203-206 also appeared to contribute to binding. These findings reinforce the conformational importance of PrP-PrP interactions and suggest potential mechanisms by which existing and new therapeutics may act by inhibiting interactions at these sites.

In the final portion of this work we develop anti-prion antibodies for increased therapy. By yeast surface display affinity maturation, we isolated ICSM18 mutants with a greater than 300 fold increase in affinity for both recombinant PrP and for native PrP expressed by a mouse nueroblastoma cell line. When these antibodies were expressed by cells persistently infected with prions the improved affinity antibody fragments showed reduced levels of PrP in the disease conformation compared to the cells expressing the parental antibody fragment. We also developed new lead candidate antibody fragments that bind to the helix2-helix3 region that may play a role in PrPC to PrPSc conversion, and are useful for structural characterization and as potential therapeutics.

Overall, a method was developed for amino-acid level characterization of protein-protein interactions and this method was applied to understand factors that contribute to PrP self-associations relevant to disease pathology and to identify the mechanism by which antibodies recognize PrP relevant to disease treatment.

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40

Parham, Steve Neil. "Saccharomyces cerevisiae Sup35p and its prion-like behaviour." Thesis, University of Kent, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246643.

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41

Roostaee, Alireza. "Importance of dimerization in aggregation and neurotoxicity of Prion and [alpha]-Synuclein in prion and Parkinson's diseases." Thèse, Université de Sherbrooke, 2012. http://hdl.handle.net/11143/6650.

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Abstract: Neurodegenerative diseases are associated with progressive loss of structure or function of neurons which results in cell death. Recent evidence indicate that all neurodegenerative disorders, sporadic or transmissible, may have a common pathological mechanism at the molecular level. This common feature consists of protein aggregation and accumulation of harmful aggregates in neuronal cells resulting in cellular apoptosis and neurotoxicity. Neurodegenerative diseases can affect abstract thinking, skilled movements, emotional feelings, cognition, memory and other abilities. This diverse group of diseases includes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), prion diseases or transmissible spongiform encephalopathies (TSEs) and amyotrophic lateral sclerosis. In my project I worked on the molecular mechanism of protein aggregation, propagation and neurotoxicity in Parkinson's disease and prion disease. Prion disease and PD are associated with misfolding and aggregation of PrPc and a-Synuclein (a-Syn), respectively. Despite being two important neurodegenerative disorders, molecular mechanisms of a-Syn or PrPC aggregation and amyloidogenesis are still unclear in PD and prion disease. Furthermore, the toxic protein species in PD have not been characterized yet. In this study we characterize the mechanism of a-Syn and PrPc misfolding in a physiological-like cell free condition in the absence of a-Syn aggregates, PrPc ggregated isoform (Pre's), denaturants or acidic environment. A number of studies indicate that dimerization of PrPc or a-Syn may be a key step in the aggregation process. To test this hypothesis we verified if enforced dimerization of PrPc or a-Syn may induce a conformational change reminiscent of the conversion of PrPc or a-Syn to PrPR' or a-Syn aggregates, respectively. We used a well-described inducible dimerization strategy where a dimerizing domain called FK506-binding protein (Fv) was fused to PrPc or a-Syn in order to produce chimeric proteins Fv-PrP and a-SynF'''. A divalent ligand AP20187 was used to induce protein dimerization. Addition of AP20187 to recombinant Fv-PrP in physiological-like conditions resulted in a rapid conformational change characterized by an increase in beta-sheet (13-Sheet) structure and simultaneous aggregation of the proteins. However, non-dimerized PrP formed 13-Sheet conformation in very slower rates. In the presence of AP20187, we also report a rapid random coil into 13-sheet conformational transformation of a-SynF" within 24 h, whereas wild type a-Syn showed 24 h delay to achieve P-sheet structure after 48 h. Electron microscopy experiments demonstrated that dimerization induced amyloid fibril formation after 48 h for both Fv-PrP and a-Syr?", whereas in the absence of dimerizing ligand AP20187, PrP or a-Syn converted into amyloid fibrils after 3 days or even later. Dimerization-induced Fv-PrP aggregates were partially resistant to PK digestion which is a characteristics of the naturally occurring PrPR'. The rates of amyloidogenesis in the presence of dimerization was also characterized by Thioflavin T (ThT) fluorescence probing. Whereas the stable structure of Fv-PrP showed no ThT binding for over 60 h of incubation at 37°C, the addition of AP20187 to Fv-PrP resulted in a time-dependent increase in ThT binding. As for a-SynR, dimerization accelerated the rate of ThT binding and amyloid formation comparing to the slower amyloidogenesis rate of wild type a-Syn in the absence of dimerizer AP20187. The impact of dimerization on a-Syn aggregation was further determined by Fluorescence ANS probing, indicating a higher affinity of dimerization-induced a-SynF" aggregates for binding to ANS comparing to wild type a-Syn aggregates. These results indicate that dimerization increases the aggregation and amyloidogenesis processes for Fv-PrP and a-SynF". Both Fv-PrP and a-SynF" amyloids were successfully propagated in vitro by protein misfolding amplification (PMCA) cycle. These results ar in agreement with the theory that all protein aggregates in neurodegenerative diseases propagate with the same molecular mechanism. Neurotoxicity of recombinant Fv-PrP and a-SynF" aggregates was determined in cellulo and in vivo, respectively. Aggregates of Fv-PrP were toxic to cultured cells whilst soluble Fv-PrP and amyloid fibres were harmless to the cells. When injected to the mice brain, both a-Syni" and a-Syn pre-fibrillar aggregates internalized cells and induced neurotoxicity in the hippocampus of wild-type mice. These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by PMCA method, providing the first evidence for the in vitro propagation of synthetic a-Syn aggregates. These results suggest an important role for protein dimerization in aggregation and amyloidogenesis, and therefore, in the pathology of PD and prion disease. The similarities between aggregation, amyloidogenesis and toxicity of PrPC and ct-Syn provide further evidence on the existance of a prion-like mechanism in all neurodegenerative disorders. // Résumé: Les maladies neurodégénératives sont associées à la perte progressive des propriétés structurales ou fonctionnelles des neurones, ce qui engendre la mort des cellules. De récentes études indiquent que tous les désordres neurodégénératifs, sporadiques ou transmissibles, peuvent avoir un mécanisme pathologique commun au niveau moléculaire. Ce dispositif commun se compose de l'agrégation de protéines, de la propagation des agrégats, et de l'accumulation d’agrégats toxiques dans les cellules neuronales, menant à l'apoptose et à la neurotoxicité cellulaire. Les maladies neurodégénératives peuvent affecter la pensée abstraite, les mouvements habiles, les sentiments émotifs, la connaissance, la Mémoire et d'autres capacités cognitives. Ce groupe divers de maladies inclut la maladie d'Alzheimer (AD), de Parkinson (PD), de Huntington (HD), les maladies à prions ou encéphalopathies spongiformes transmissibles (TSEs) et la sclérose latérale amyotrophique (ALS). [symboles non conformes]
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42

Fioriti, Luana. "The role of abnormal forms of the prion protein in the pathogenesis of inherited prion diseases." Thesis, Open University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421998.

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43

Lennon, Christopher William. "Probing Isoforms of the Prion Protein through Tyrosine Nitration." The University of Montana, 2007. http://etd.lib.umt.edu/theses/available/etd-08282007-194643/.

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The prion protein (PrP) has multiple stable isoforms. When PrP misfolds, it aggregates and causes neurological disease and death in mammals. The structure of the non-pathogenic isoform has been determined while the structures of the disease related isoforms are unknown. The nitration labeling patterns of three PrP isoforms with peroxynitrite and tetranitromethane, as detected by mass spectrometry, are reported. Two conserved tyrosine residues (tyrosines 149 and 150) are not labeled by either reagent in the normal cellular form of the prion protein but these residues become reactive after the protein has been converted to one of two aggregated isoforms. Another difference observed is that two other conserved tyrosine residues, 225 and 226, are much less reactive in both aggregated isoforms, while all other tyrosine residues show virtually no isoform specific-labeling. Thus, two regions been identified in which Tyr residues undergo a change in solvent accessibility, which may be due to a conformational change in that region or to inter-subunit packing.
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44

Bounhar, Younes. "The prion protein protects against Bax-mediated cell death /." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29415.

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The prion protein (PrP) is known for its implication in a number of neurological disorders. Interestingly, overexpression of Bcl-2 in these PrP-/- cells protects against serum deprivation, suggesting that PrP may function like Bcl-2 to prevent cells from undergoing apoptosis.
Based on this idea, this thesis demonstrates that PrP is a potent protective agent against Bax-mediated death of cultured human primary neurons. This neuroprotective function appears to require the presence of the octapeptide repeat region of PrP. Surprisingly, while the majority of PrP resides on the cell surface as a glycophosphatidyl inositol (GPI)-anchored protein, the GPI anchor is not required for the neuroprotective function of PrP. In contrast, PrP needs trafficking past the cis-Golgi to be effective against Bax since its neuroprotective function is sensitive to brefeldin A and monensin treatments.
On the other hand, we have established a yeast-based assay to analyse the function of PrP against Bax. (Abstract shortened by UMI.)
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45

Klewpatinond, Mark. "Spectroscopic investigation of metal binding to the prion protein." Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500024.

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46

Landy, Timothy Adam. "Aspects of prion protein dynamics in cell culture models." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444919/.

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The cell biology of Prion formation and transfer is not well understood. In order to further elucidate the dynamics of PrPc and PrPsc in a cellular context, fusions between Green Fluorescent Protein (GFP) and PrP were constructed and infected/uninfected cell line pairs expressing these constructs were created. Biochemical analysis indicated that the C-terminal PrPc portion of the fusion protein successfully converted to PrPsc. However, further studies demonstrated that proteolysis occurs between GFP and PrP and therefore the fusion protein cannot be employed as a direct reporter for PrPsc. A Time-Lapse microscopy system was set up and studies were undertaken with infected and uninfected cell lines expressing the fusion construct or cytoplasmic markers to observe events that may be related to transfer of infectivity. Although no exchange of fusion protein is observed, cytoplasmic material is released from both infected and uninfected cell lines. Fluorescence recovery after photobleaching (FRAP) was carried out to establish a system for further investigation of PrP dynamics in the plane of the membrane. Early experiments indicate the possibility of a difference in the diffusion of PrP between infected and uninfected contexts. It is not currently known how Prion glycoform profile is transmitted and maintained following a new infection. The glycoform profile of PrPscwas perturbed in order to investigate the causal role of PrPsc glycotypes in transmission and maintanence of Prion glycoform profile. The results indicate that perturbation of PrPsc glycoform profile in an infectious source does not lead to a correlated perturbation of glycoform profile in the newly established infection. Therefore the glycosylation of PrPsc in an infectious source is not a required source of information for establishing the glycoform profile of a Prion infection.
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47

Lawrence, Clare Louise. "Factors affecting the aggregation of yeast prion protein Sup35p." Thesis, University of Kent, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246590.

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48

Jenkins, David Christopher. "Equilibrium and kinetic folding studies of the prion protein." Thesis, University of Warwick, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443621.

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49

Soto, Renou Emma Nadia. "Design, synthesis and selection of prion protein affinity ligands." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619972.

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50

Moore, Richard C. "Gene targeting studies at the mouse prion protein locus." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/11184.

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The prion protein (PrPc) is a normal host-encoded glycoprotein which accumulates as a disease specific protease-resistant isoform (PrPsc) in the brains of infected hosts. In a number of species PrP polymorphisms and germline mutations are associated with the modulation of disease phenotype and the occurrence of familial prion disease. To investigate the biological consequences of manipulation of the prion protein in mice a flexible two step double replacement gene targeting strategy was developed. This method can be used to generate a series of mouse lines with alterations to the mouse prion protein gene (Prn-p). To facilitate gene targeting studies a restriction map of the 129/Ola Prn-p locus was constructed and a series of overlapping genomic clones were retrieved from a λ DASH II bacteriophage 129/Ola library. The double replacement strategy was used to generate PrP deficient mice and mice with subtle alterations to PrP codons 108 and 189. Murine PrP 108F/V_189L/T dimorphisms give rise to 2 distinct PrP allotypes, PrP-A and PrP-B and these are postulated to be responsible for the control of incubation time following challenge with a wide range of prion inocula. To test this proposal the endogenous 129/Ola PrP-A allotype [108L_189T] was converted by gene targeting to encode the PrP-B allotype [108F_189V]. Mice bearing codon 108 and 189 alterations were challenged with mouse adapted BSE isolate 301V. Gene targeting in 129/Ola derived HM-1 ES cells and breeding with 129/Ola mice enabled the investigation of the effect of PrP alterations in the absence of PrP overexpression artefacts or the influence of non-Prn-p genes. The dramatic acceleration of incubation time in mice homozygous for the Prn-pa[108F_189V] gene targeted allele confirmed the major role of codons 108 and 189 in the control of BSE isolate 301V incubation time - and probably other prion isolates. This data provides the strongest evidence yet that the incubation time control, long attributed to the action of different alleles of Sinc (Prn-i), is determined by PrP codon 108L/F and 189T/V dimorphisms.
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