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研究生:沈志豪
研究生(外文):Chih-Hao Shen
論文名稱:研究倉鼠普立昂蛋白纖維之澱粉樣核心區
論文名稱(外文):Exploring the Amyloid Core Region of Hamster Prion Fibrils
指導教授:陳佩燁
口試委員:廖永豐陳韻如
口試日期:2015-07-27
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生化科學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:171
中文關鍵詞:普立昂疾病澱粉樣纖維倉鼠普立昂蛋白交互引晶澱粉樣核心區種間屏障
外文關鍵詞:prion diseasesamyloid fibrilshamster prion proteincross-seedingamyloid corecross-β structure
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普立昂疾病為一類具傳染性且致命的神經退化疾病,主要發生於人類和其他哺乳動物。而在普立昂疾病的研究當中,α-螺旋結構為主的 PrP(C) 因錯誤摺疊而轉變為富含 β-摺板之異構體 PrP(Sc) 的分子機制以及普立昂蛋白在不同物種間會產生之種間屏障是目前仍未解開的兩大謎團。根據『單一蛋白學說(protein-only hypothesis)』,錯誤摺疊的普立昂蛋白會快速並具規則性堆疊形成類澱粉纖維之結構。由於類澱粉纖維的形成是在普立昂疾病當中一個重要的特徵,因此藉由研究構成普立昂蛋白纖維核心之 cross-β 結構時所利用的關鍵序列,便可深入了解種間屏障的分子原理與類澱粉纖維核心在普立昂蛋白構形轉變時所扮演的角色。 本研究利用大腸桿菌表現出重組之全長倉鼠普立昂蛋白(簡稱為 SHaPrP(23-231))以及利用固相化學合成法合成出倉鼠普立昂胜肽片段,分別是 SHaPrP(108-144)、SHaPrP(108-127)、SHaPrP(128-144)、SHaPrP(172-194) 與 SHaPrP(200-227) 五個片段。以螢光分子 Thioflavin T (ThT)為主,圓二色光譜(CD)為輔,來研究類澱粉纖維之形成動力學。將普立昂胜肽片段和全長普立昂蛋白進行交叉引晶試驗,結果發現胜肽片段 SHaPrP(108-144)、SHaPrP(108-127)、SHaPrP(172-194) 和 SHaPrP(200-227) 所形成之類澱粉纖維當作晶種時,對全長重組蛋白 SHaPrP(23-231) 有引晶效果,表示這幾個區域在 SHaPrP(23-231) 形成類澱粉纖維時扮演關鍵的角色。反之,將SHaPrP(23-231) 之類澱粉纖 維當作晶種,對胜肽片段 SHaPrP(108-144) 和 SHaPrP(108-127) 有引晶效果,但是對 SHaPrP(128-144) 則無。此結果顯示全長重組倉鼠普立昂蛋白形成類澱粉纖維時是利用 108-127 這個序列當作核心而不是 128-144。這個結果和先前研究的假說一致,認為倉鼠和小鼠之間在普立昂的傳染時有種間屏障,可能是因為兩物種之普立昂蛋白在形成類澱粉纖維時,所利用的核心不同所致。另外,我們的研究結果也顯示了全長重組倉鼠普立昂蛋白存在著三段澱粉樣核心區,一個在普立昂蛋白中心疏 水區的 108-127,另外兩個在 C 端之 α-螺旋區的 172-194 以及 200-227。

The prion diseases are transmissible fatal neurodegenerative disorders affecting human and other mammals. One of the crucial molecular events is the conformational conversion of the normal, membrane-anchored prion protein PrP(C) into the β-sheet-rich and misfolded isoform, PrP(Sc). Within the context of the “protein only” hypothesis, the PrP(Sc) can associate each other to form fibril-like structure. However, the molecular mechanisms underlying the conversion of PrP(C) to the PrP(Sc) form and species barrier remain unclear. Since amyloid formation is a key hallmark of prion pathogenesis, studies of prion protein segment involved in the formation of cross-β structure have provided molecular details of species barrier and insights of amyloid core. The full-length recombinant Syrian hamster prion protein (SHaPrP(23-231)) was produced by E. coli over-expression and five chemically synthetic peptides, SHaPrP(108-144), SHaPrP(108-127), SHaPrP(128-144), SHaPrP(172-194), and SHaPrP(200-227) were produced by solid-phase peptide synthesis. The amyloidogenesis of SHaPrP protein and peptides was investigated in vitro by Thioflavin T (ThT) assay mainly and circular dichroism (CD) spectroscopy. The cross-seeding capacity between SHaPrP protein and peptide fibrils was used to identify the amyloid core region. We found that short peptide SHaPrP(108-144), SHaPrP(108-127), SHaPrP(172-194), and SHaPrP(200-227) fibrils as seed have seeding effect for SHaPrP(23-231) monomer, suggesting that these regions are critical in the amyloidogenesis of SHaPrP(23-231). The full-length recombinant SHaPrP(23-231) fibrils as seed could induce the fibril formation of short peptide SHaPrP(108-144) and SHaPrP(108-127) but not for SHaPrP(128-144). These results suggest that SHaPrP(108-127) segment but not SHaPrP(128-144) segment is involved in the amyloid core of SHaPrP fibrils. This result corresponds to our previous hypothesis that the species barrier between SHaPrP and MoPrP is contributed by utilization of difference amyloid core of PrP. Moreover, this work provides evidence that amyloid core of SHaPrP fibrils is involved in hydrophobic region of residue 108-127 and helical region of residue 172-194 and 200-227.

謝誌 i
中文摘要 iii
Abstract v
Abbreviations vii
Contents xi
Figure contents xiv
Table contents xvii


Chapter One: Introduction 1
1.1 Introduction to prion disease 3
1.2 The structural studies of prion protein 8
1.3 PrPSc is amyloid 12
1.4 Critical region of PrP in amyloidogenesis 17
1.5 Interspecies transmissibility of prions 22
1.6 Species barrier between hamster and mouse 26
1.7 Aim of this Thesis 33

Chapter Two: Materials and Methods 37
2.1 Materials 39
2.1.1 Water 39
2.1.2 Chemical 39
2.1.3 Laboratory instruments 43
2.2 Methods 46
2.2.1 Solid-phase peptide synthesis 46
2.2.2 Peptide purification and identification 47
2.2.3 HPLC quantification of peptides 48
2.2.4 Protein expression construct and transformation of bacterial cells 48
2.2.5 Small-scale protein expression 51
2.2.6 Large-scale protein expression, purification, and identification 51
2.2.6.1 Glycerol cell stock preparation 51
2.2.6.2 Induction of SHaPrP expression and isolation of inclusion bodies 52
2.2.6.3 Immobilized metal-ion affinity chromatography (IMAC) 52
2.2.6.4 Desalting and oxidative refolding for SHaPrP 53
2.2.6.5 HPLC purification and protein identification 53
2.2.7 ThT fluoromeric assay of amyloidogenesis 54
2.2.8 CD analysis of secondary structure 55
2.2.9 TEM observation of fibril morphology 56
2.2.10 Seed preparation for the seeding assay 56
2.2.11 SHaPrP PK-digested seed preparation 56
2.2.12 Seeding assay 57
2.2.13 Data analysis 57

Chapter Three: Results (I)-Sample Preparation 59
3.1 Synthesis, purification, and identification of peptides 61
3.2 Quantification of peptides by HPLC 66
3.3 Codon optimization for recombinant PrP protein 68
3.4 Small-scale protein expression analysis 72
3.5 Large-scale protein expression 74
3.6 IMAC purification, desalting, and disulfide-bond formation 76
3.7 HPLC purification and protein identification 80

Chapter Four: Results (II)-Spontaneous Amyloidogenesis 85
4.1 Spontaneous fibril formation of SHaPrP peptides 87
4.2 Spontaneous fibril formation of SHaPrP protein 101
4.3 SHaPrP peptides and protein seed preparation 104

Chapter Five: Results (III)-Seeding Assay 109
5.1 Homologous seeding for SHaPrP protein and peptides 111
5.2 Heterologous seeding capacity of amyloidogenesis using SHaPrP peptides as seed and SHaPrP as substrate 118
5.3 Heterologous seeding capacity of amyloidogenesis using SHaPrP as seed and SHaPrP peptides as substrate 121

Chapter Six: Discussion 131
6.1 Overview 133
6.2 Sample preparation (Chapter 3) 134
6.3 Spontaneous amyloidogenesis (Chapter 4) 135
6.4 Seeding assay (Chapter 5) 137

Chapter Seven: Conclusions and Future Works 141

Appendix 147
References 159



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