研究生: |
温時雨 Wen, Shih-Yu |
---|---|
論文名稱: |
脯胺酸和羥脯胺酸組成之胜肽短鏈對貝它類澱粉蛋白Aβ(14-25)聚集的探討 The effects of polyproline and poly(hydroxyproline) on Aβ(14-25) aggregation |
指導教授: |
洪嘉呈
Horng, Jia-Cherng |
口試委員: | |
學位類別: |
碩士 Master |
系所名稱: |
理學院 - 化學系 Department of Chemistry |
論文出版年: | 2010 |
畢業學年度: | 98 |
語文別: | 中文 |
論文頁數: | 74 |
中文關鍵詞: | 貝它類澱粉蛋白 、Aβ 的抑制 |
外文關鍵詞: | Aβ(14-25), Alzheimer's disease |
相關次數: | 點閱:2 下載:0 |
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阿茲海默症是神經退化性疾病的一種主要疾病,其主要的病理特徵是神經細胞內纖維化糾結以及腦細胞外老年斑塊,而貝它類澱粉蛋白的聚集則是造成老年斑塊的主要原因。儘管貝它類澱粉蛋白已經受到廣泛的研究,但目前其沉積聚集的機制還尚未清楚。本次實驗在探討脯胺酸及脯胺酸衍生物所組成的短胜肽鏈對於貝它類澱粉蛋白的影響。
本研究中,我們選擇貝它類澱粉蛋白中最重要的一段胺基酸序列 14-25 ( HQKLVFFAEDVG ) 來做研究,合成一系列接上聚脯胺酸或聚脯胺酸衍生物之胜肽鏈共五段 : 未接上脯胺酸 (WT-Aβ (14-25)),在碳端的位置接上六個脯胺酸 (Aβ (14-25)-(Pro)6)、順式羥脯胺酸 (Aβ (14-25)-(hyp)6) 以及反式羥脯胺酸 (Aβ (14-25)-(Hyp)6),另外製備一胜肽,在氮端和碳端的位置上各接上六個反式羥脯胺酸 ((Hyp)6-Aβ (14-25)-(Hyp)6)。利用螢光光譜儀、穿透式電子顯微鏡以及圓二色光譜儀來探討這些胜肽鏈是否對 Aβ 沉積具有抑制的效果。最後在將這些胜肽鏈與 WT-Aβ (14-25) 混合,然後觀察其抑制類澱粉沉澱之情形。
經由螢光光譜和 TEM 的測量,我們可以知道在 Aβ (14-25) 的碳端位置接上六個脯胺酸以及羥脯胺酸都可以抑制類澱粉纖維的產生,而且羥脯胺酸抑制效果比脯胺酸還要好。然而當這些接有聚脯胺酸或聚脯胺酸衍生物的 Aβ 胜肽與原生 Aβ 胜肽混合後,並無抑制的效果。
1.Bella, J., and Eaton, M. (1994) Crystal and molecular structure of a collagen-like peptide at 1.9 Å resolution, Science 266, 75-81.
2.Stefani, M., and Dobson M. C. (2003) Protein aggregation and aggregate toxicity:new insights into protein folding, misfolding diseases and biological evolution, J. Mol. Med. 81, 678-699.
3.Selkoe, D. J. (2004) Cell biology of protein misfolding: The examples of Alzheimer's and Parkinson's diseases, Nat. Cell Bio. 6, 1054-1061.
4.Irvine, B. G., El-Agnaf, M. O., Shankar, M. G., Walsh, M. D. (2008) Protein aggregation in the brain : the molecular basis for Alzheimer's and Parkinson's diseases, Mol. Med. 14, 451-464.
5.Höppener, W.J., Ahrén, B., Lips, J. C. (2000) Islet amyloid and type 2 diabetes mellitus, N. Engl. J. Med. 343, 411–419.
6.Truant, R., Atwal, R. S., Desmond, C., Munsie, L., and Tran, T. (2008) Huntington’s disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases, FEBS Journal 275, 4252-4262.
7.Fradinger, E. A., Monien, H. B., Urbanc, B., Lomakin, A., Tan Miao, Li Huiyuan, Spring, M. S., Condron, M. M., Cruz, L., Xie Cui-Wei, Benedek, B. G., and Bitan, G. (2008) C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity, Proc. Natl. Acad. Sci. 105, 14175-14180.
8.Soto, C., Sigurdsson, E. M., Morelli, L., Asok Kumar, R., Castano, E. M., and Frangione, B. (1998) β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis : Implications for Alzheimer's therapy, Nat. Med. 4, 822-826.
9.Sciarretta, K. L., Boire, A., Gordon, D. J., and Meredith, S. C. (2006) Spatial Separation of β-Sheet Domains of β-Amyloid : Disruption of Each β-Sheet by N-Methyl Amino Acids†, Biochemistry 45, 9485-9495.
10.Jellinger, K. A. (2006) Alzheimer 100 – highlights in the history of Alzheimer research. J. Neural Transm. 113, 1603-1623.
11.洪成治. (2000) 阿茲海默氏症的基因檢測與遺傳諮詢.應用心理研究,第七期,143-155.
12.吳志偉. (2003) 腦區域性貝它糊蛋白結合蛋白之純化及其功能之研究,碩士論文,國立成功大學細胞生物與解剖學研究所.
13.Murray, M. M., Bernstein, S. L., Nyugen, V., Condron, M. M., Teplow, D. B., and Bowers, M. T. (2009) Amyloid β Protein: Aβ40 Inhibits Aβ42 Oligomerization, J. Am. Chem. Soc. 131, 6316-6317.
14.Takahashi, T., and Mihara, H. (2008) Peptide and Protein Mimetics Inhibiting Amyloid β-Peptide Aggregation, Acc. Chem. Res. 41, 1309-1318.
15.Lührs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Döbeli, H., Schubert, D., and Riek, R. (2005) 3D structure of Alzheimer's amyloid-β(1–42) fibrils, Proc. Nat. Acad. of Sci. 102, 17342-17347.
16.Tjernberg, L. O., Nāslund, J., Lindqvist, F., Johansson, J., Karlstromi, A. R., Thyberg, J., Terenius, L., and Nordstedt, C. (1996) Arrest of β-Amyloid Fibril Formation by a Pentapeptide Ligand. J. Biol. Chem. 271, 8545-8548.
17.Wood, S. J., Wetzel, R., Martin, J. D., and Hurle, M. R. (1995) Prolines and Aamyloidogenicity in Fragments of the Alzheimer's Peptide β/A4, Biochemistry 34, 724-730.
18.Camus, M.-S., Santos, S. D., Chandravarkar, A., Mandal, B., Schmid, A. W., Tuchscherer, G., Mutter, M., and Lashuel, H. A. (2008) Switch-Peptides: Design and Characterization of Controllable Super-Amyloid-Forming Host-Guest Peptides as Tools for Identifying Anti-Amyloid Agents, ChemBioChem 9, 2104-2112.
19.Tjernberg, L. O., Callaway, D. J., Tjernberg, A., Hahne, S., Lilliehöök, C., Terenius, L., Thyberg, J., and Nordstedt, C. (1999) A Molecular Model of Alzheimer Amyloid β-Peptide Fibril Formation. J. Biol. Chem. 274, 12619-12625.
20.Merrifield, R. B. (1986) Soild phase peptide synthesis. Science 232, 341-347.
21.張湘戎. (2003) 體抑素胜肽分子內雙硫鍵建構之研究,碩士學位論文,中原大學化學研究所.
22.Shieh Jia-Min, Lai Yi-Fan, Lin Yong-Chang, and Fang Jr-Yau. (2005) Photoluminescence: Principles, Structure,and Applications. Nano Communications (NDL) 26, 28-39.
23.Skoog, A. D., Holler, F. J., Nieman, A. T. (1998) Principle of instrumental analysis 5nd ed. 335-267. Saunders College Press, Belmont.
24.Berova, N., Nakanishi, K., and Woody, R. (2000) Circular dichroism : Principles and applications. Wiley, Hoboken.
25.陳力俊、張立、梁鉅銘、林文台、楊哲人、鄭晃忠. (2004) 材料電子顯微鏡學. 全華出版社. 台灣.
26.Bhattacharyya, A., Thakur, A. K., Chellgren, V. M., Thiagarajan, G., Williams, A. D., Chellgren, B. W., Creamer, T. P., and Wetzel, R. (2006) Oligoproline Effects on Polyglutamine Conformation and Aggregation, J. Mol. Biol. 355, 524-535.
27.DeRider, M. L., Wilkens, S. J., Waddell, M. J., Bretscher, L. E., Weinhold, F., Raines, R. T., and Markley, J. L. (2002) Collagen stability : Insights from NMR spectroscopic and hybrid density functional computational investigations of the effect of electronegative substituents on prolyl ring conformations. J. Am. Chem. Soc. 124, 2497-2505.
28.Benzi, C., Improta, R., Scalmani, G., Barone, V. (2002) Quantum mechanical study of the conformational behavior of proline and 4R-hydroxyproline dipeptide analogues in vacuum and in aqueous solution. J. Comput. Chem. 23, 341-350.
29.Wolfe, S. (1972) Gauche effect. Stereochemical consequences of adjacent electron pairs and polar bonds. Acc. Chem. Res. 5, 102-111.
30.Improta, R., Benzi, C., Barone, V., (2001) Understanding the role of stereoelectronic effect in determining collagen stability. 1. A quantum mechanical study of proline, hydroxyproline, and fluoroproline dipeptide analogues in aqueous solution. J. Am. Chem. Soc. 123, 12568-12577.
31.Chiang Yi-Chun, Lin Yu-Ju, and Horng Jia-Cherng. (2009) Stereoelectronic effects on the transition barrier of polyproline conformational interconversion. Protein Science 18, 1967-1977.
32.Castelletto, V., Hamley, I. W., Cenker, C., and Olsson, U. (2010) Influence of Salt on the Self-Assembly of Two Model Amyloid Heptapeptides, J. Phys. Chem. B 114, 8002-8008.