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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林聖賢 | |
dc.contributor.author | Yen-Li Lee | en |
dc.contributor.author | 李彥莉 | zh_TW |
dc.date.accessioned | 2021-06-08T05:17:44Z | - |
dc.date.copyright | 2005-08-11 | |
dc.date.issued | 2005 | |
dc.date.submitted | 2005-08-02 | |
dc.identifier.citation | Alonso, D.O., DeArmond, S.J., Cohen, F.E., and Daggett, V. 2001. Mapping the early steps in the pH-induced conformational conversion of the prion protein. Proc Natl Acad Sci U S A 98: 2985-2989.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24177 | - |
dc.description.abstract | 中文摘要
普昂疾病是一種傳染性海綿樣腦病變症。由於90年代在英國爆發的狂牛症引發全世界對於普昂疾病的關注,科學家們普遍懷疑此類疾病可能是直接經由牛傳染到人。至今只知道正常狀態的PrPC 被誘變成致病狀態的PrPSc 為普昂疾病的致病原因。然而,引起此結構的轉變機制目前仍是個謎。為研究普昂疾病跨越「種族屏障」,使不同物種之間發生交叉感染的現象。我們以老鼠和大頰鼠為研究對象,截取PrP普遍認為最重要的一段胺基酸序列(108-144)為模型,成功地量測到老鼠與大頰鼠間「種族屏障」的數值約大於同物種間的5倍。另外,實驗結果指出PrP第139號殘基不僅影響物種間交互感染的難易度,且對於纖維生成之快慢極具影響。我們將大頰鼠139號殘基的甲硫胺酸置換成異白胺酸,此突變之普昂纖維能成功地跨越種族屏障,並感染老鼠的普昂蛋白。然而,若將老鼠138號殘基的異白胺酸突變成甲硫胺酸,胺基酸序列(109-112)在普昂纖維與自然的普昂蛋白間的一致性,能有效降低老鼠與大頰鼠間的種族屏障。 由於先前的研究指出人類PrP129號殘基呈現胺基酸多型性(M129V)的特質, 此特質不但影響了人類對普昂疾病的敏感度,且患者呈現截然不同的致病表型。對此,我們亦利用普昂胜肽系統,探討多型性特質影響人類受牛隻普昂纖維感染性的差異。研究指出,甲硫胺酸同型結合子(huPrP129MM)的普昂胜肽與牛隻普昂纖維間的種族屏障最低,這項發現與先前的研究結果吻合- 因狂牛症而感染變異型庫賈氏症的人目前皆為PrP129號殘基甲硫胺酸同型結合子。另一方面,我們亦探討多型性特質在自發性纖維化(spontaneous fibrillizaiton)的過程中所扮演的角色,發現(異白胺酸/甲硫胺酸)異型結合子形成普昂纖維所需要的遲滯時間(lag time)最長,甲硫胺酸與異白胺酸可能在此過程中,相互競爭同一個結合部位(binding site)。 此結果說明了為何人類的偶發性庫賈氏症以具有甲硫胺酸或異白胺酸同型結合子的人居多。 | zh_TW |
dc.description.abstract | Abstract
Prion diseases comprise a group of neurodegenerative transmissible spongiform encephalopathies (TSE). The epidemic of mad cow disease happened in England in 1990s and its recent spread to humans have received broad attention all over the world. Although the pathogenesis of the prion diseases is not completely disclosed so far, it has been known that the drastic structural transition from native PrPC to abnormal pathogenic PrPSc leads to the prion diseases. However, the transmission of the prion diseases was found to be species-specific. In order to study the species barrier of the prion transmission, prion peptides corresponding to hamster PrP sequence 108 to 144 and mouse PrP sequence 107 to 143 were used as a model system. We established a system to quantify the transmission barrier and to examine how sequence difference affects the transmission efficiency. The transmission barrier between mouse and hamster prion peptides was found to be about 5 times higher than the homologous transmission. In addition, residue 139 plays a critical role in the seeding specificity. The energy barrier prevents mouse from infection with hamster fibrils can be abolished by a single mutation at residue 139 with isoleucine substituted for methionine in the hamster fibrils. However, an I139→M mutation in the mouse fibrils still has strong seeding barrier to the hamster prion peptide while the same fibrils can induce the fibrillization of the mouse prion peptide easily. In this case, the homology within the region spanning residue 109-112 turns into the principal factor for determining the seeding specificity of the prion fibrils. Moreover, the human prion gene presents a polymorphism at the codon 129, resulting in either methionine or valine. The previous studies showed that this polymorphism has a profound effect on the susceptibility and pathological phenotype of the human prion disease. In this study, we also evaluated the influence of this polymorphism in the transmission efficiency between bovine and human using the same peptide model system. Our finding suggested that the methionine homozygote has higher susceptibility to the bovine PrP fibrils whereas the Val homozygote is resistant to the TSE infection. Finally, our studies in the fibrillization kinetics of the human prion peptides showed that the co-existence of the huPrP129MM and huPrP129VV peptides would retard the nucleation rate compared with the homozygous ones. The interference effect indicated that the heterozygote disfavored amyloid formation and explained why most of the sCJD patients are 129 homozygotes at the codon 129. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T05:17:44Z (GMT). No. of bitstreams: 1 ntu-94-R92223031-1.pdf: 5647360 bytes, checksum: 99327c14e0739c475e70e06dd8073cf6 (MD5) Previous issue date: 2005 | en |
dc.description.tableofcontents | Table of Content
Abbreviations i Abstract iv 中文摘要 vi Chapter 1 Introduction 1.1 Introduction to prion disease 1 1.2 The 3D structural studies of prion protein 5 1.3 Mechanistic Models of amyloid fibril formation 7 1.4 Unraveling the conformational conversion of PrPC to PrPSc using synthesized peptide 9 1.5 Previous studies about species barrier for interspecies transmissibility of prions 11 1.5.1 Species barrier between mouse and hamster 13 1.5.2 Species barrier between human and bovine 15 1.6 The aim of this project 20 Chapter 2 Material and Methods 2.1 Materials 21 2.1.1 General 21 2.1.2 Chemical 22 2.2 Methods 23 2.2.1 Peptide synthesis, purification and identification 23 (1) Solid phase peptide synthesis 23 (2) Peptide purification and identification 26 2.2.2 Fibrillogenesis of the prion peptide monitored by Circular Dichrosim (CD) spectroscopy 26 (1) Time course of amyloid fibril formation for MMM, MMI, LVI, and LVM 26 (2) Evaluation of the species barrier among MMM, LVI, MMI, and LVM 27 (3) Fibrillization time course for huPrP129MM, huPrP129MV, and huPrP129VV 28 (4) Estimation of the species barrier among huPrP129MM, huPrP129MV, huPrP129VV and bPrP 29 2.2.3 Time course of amyloid fibril formation monitored by Thioflavin T (ThT) fluoromeric assay 29 (1) Temperature dependent fibrillization time course for MMM and LVI 30 (2) ThT fluorescence emission spectra for MMM, LVI, LVM, and MMI 30 2.2.4 Fibrillogenesis monitored by light scattering 30 2.2.5 Transmission Electron Microscope (TEM) 31 2.2.6 Time-correlated single-photon counting fluorescence spectroscopy 31 Chapter 3 Results and Discussions 3.1 Mechanistic models for formation of PrP-res from PrPC 32 3.2 Kinetic analysis of the nucleation phase of the nucleation-dependent polymerization model 36 3.3 Kinetics of the structural conversion of the prion peptide 41 3.3.1 Structural conversion of the prion peptide during fibrillization process monitored by CD spectroscopy 41 3.3.2 Temperature dependence of the apparent nucleation rate for MMM and LVI 43 3.4 Critical residues in determining the kinetics of amyloid fibiril formation 47 3.5 Thioflavin T (ThT) fluorescence assay upon binding to the amyloid fibrils of the prion peptides 52 3.6 Transmission barrier between hamster and mouse 58 3.6.1 Kinetics of spontaneous and self-seeded conversion of the prion peptides 58 3.6.2 Seeding specificity for prion transmission is strongly sequence-dependent 59 3.7 A potentially crucial role for residue 138/139 in determining the species-dependent seeding specificity 67 3.8 The relationship of TSE susceptibility with the PRNP 129 homozygous genotype of human 75 3.9 Investigation of the transmission barrier from bovine to human 77 Chapter 4 Conclusions and future outlook 81 References 85 | |
dc.language.iso | en | |
dc.title | 普昂胜肽形成類澱粉樣纖維之研究 | zh_TW |
dc.title | Studies of the amyloid fibril formation of the prion peptides | en |
dc.type | Thesis | |
dc.date.schoolyear | 93-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 陳佩燁 | |
dc.contributor.oralexamcommittee | 陳振中,楊健志 | |
dc.subject.keyword | 普昂胜肽,狂牛症,種族屏障,普昂纖維, | zh_TW |
dc.subject.keyword | prion,amyloid fibril,PrP,species barrier,BSE,vCJD, | en |
dc.relation.page | 95 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2005-08-04 | |
dc.contributor.author-college | 理學院 | zh_TW |
dc.contributor.author-dept | 化學研究所 | zh_TW |
顯示於系所單位: | 化學系 |
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