Prions是一種具有傳染力,且能夠造成致命性神經衰退疾病的病原體。此類疾病發生的原因有可能是透過基因突變、傳染或是偶然的情況所造成的。例如牛海綿狀組織腦病(BSE)、庫賈氏症(CJD)、羊瘙癢症(scrapie)、及阿茲海默症(Alzheimer`s disease)等皆是屬於prions所造成的疾病。這一類疾病的特性,主要是由於腦部累積了不正常摺疊的prion蛋白質(PrP),稱為PrPsc。其中,PrPsc是正常的PrP(PrPc)經由結構上轉變而產生的。然而,某些遺傳性PrP的突變顯示,在缺乏PrPsc的情況之下,也會造成神經衰退疾病。取而代之的,是一種穿透膜形式的PrP,稱為ctmPrP。但是到目前為止,關於神經衰退與ctmPrP之間的關係,及ctmPrP在結構上的變化並不是非常的清楚。在我們的研究裡,我們在三維晶格模型中設計25個胺基酸來模擬ctmPrP在內質網膜內TM1序列的結構轉變。此外,我們也預測PrP濃度與摺疊時間的關係,並與Prusiner的基因轉殖鼠的潛伏期實驗比較,以確保我們所設計的模型之準確性。
Prions are infectious pathogens that cause a group of fatal neuro- degenerative diseases. Prion diseases can be infectious, sporadic and genetic mutation. The infectious forms of these diseases including bovine spongiform encephalopathy (BSE), Crutzfeldt-Jakob disease (CJD), scrapie of sheep, and Alzheimer`s disease, are usually characterized by the accumulation in the brain of the transmissible pathogen, an abnormally folded prion protein (PrP) termed PrPsc. PrPsc is the isoform of the normal, cellular PrP termed PrPc. However, some inherited PrP mutations appear to cause neurodegeneration in the absence of PrPsc, instead of a transmembrane form of PrP termed ctmPrP. At present, neither the relationship between the neurodegeneration and ctmPrP nor the conformation of ctmPrP has remained clear. In our simulation, we have designed a sequence composed of 25 amino acids in 3D lattice model to simulate the transformation of TM1 in the endoplasmic reticulum membrane. Furthermore, we also have simulated the correlation between the concentration of PrP and folding time. To insure that our simulations models are correct, we have compared our results with Prusiner’s incubation times of the experiments on transgenic mice.
參考文獻
1、Prusiner, S. B. (1982). Science 216, 136–144.
2、James, T. L., Liu, H., Ulyanov, N. B., Jones, S. F., Zhang, H., Donne, D,G., Kaneko, K. Groth, D., Mehlhorn, I., Prusiner, S. B., & Cohen, F. E. (1997) Proc. Natl. Acad. Sci. USA 94, 10086–10091.
3、Brandner, S., Raeber, A., Sailer, A., Blattler, T., Fischer, M., Weissmann, C. & Aguzzi, Adriano. (1996). Proc. Natl. Acad. Sci. USA. 93, 13148–13151.
4、Cohen, F. E.,& Prusiner, S. B. (1998) Annu. Rev, Biochem. 67, 793-819.
5、Prusiner, S. B, in Prion Biology and Diseases, edited by S.B. Prusiner (Cold spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999) p21.
6、Goldfarb, L. G. (2002) Microbes Infect. 4, 875–882.
7、Gajdusek, D. C., Gibbs C. J., & Alpers, M. (1966) Nature 209, 794-796
8、Prusiner, S. B, in Prion Biology and Diseases, edited by S.B. Prusiner (Cold spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999) p.465-507
9、理查。羅德斯 著;汪仲 & 張定綺 譯。致命的盛宴 1998年第二版,時報文化出版
10、三思科學電子雜誌 (2002),第9-15期。
11、Prusiner, S. B, in Prion Biology and Diseases, edited by S.B. Prusiner (Cold spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999) p1-65.
12、Prusiner , S. B. (1998) Proc. Natl. Acad. Sci. USA. 95, 13363-13383.
13、Griffith, J. S. (1967). Nature 215, 1043-1044.
14、Prusiner, S. B, in Prion Biology and Diseases, edited by S.B. Prusiner (Cold spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999) p113-145.
15、Prusiner, S. B. (1996) Trends. Biochem. Sci. 21, 482-487.
16、Prusiner, S. B, in Prion Biology and Diseases, edited by S.B. Prusiner (Cold spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999) p420-421.
17、A.P.H.I.S Safeguarding American Agriculture Feb 2002.
18、Stekel, D, J., Nowak, M. A., & Southwood, T. R. E. (1996) Nature(London) 381, 119-119.
19、Prusiner, S. B, in Prion Biology and Diseases, edited by S.B. Prusiner (Cold spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999) p.431-463.
20、楊繼江編著. 病毒學概論. 第十二章 病毒的演化與未來的展望;第十三章 病毒的細胞培養與相關技術。 2001年初版,藝軒圖書出版社.
21、Alper, T., Haig, D. A., & Clarke, M. C. (1966) B.B.R.C. 22, 278-284
22、Merz,P. A., Somerville, R. A., Wisniewski, H. M., & Iqbal, K. (1981) Acta Neuropathol (Berl). 54, 63–74.
23、Merz, P.A., Kascsak, R. J., Rubenstein, R., Carp, R. I., & Wisniewski, H. M. (1987) J. Virol .61, 42–49.
24、Bolton, D. C., Meyer, R. K., & Prusiner, S. B. (1985) J. Virol. 53, 596-606.
25、Prusiner, S. B., Mckinley, M. P., Bowman, K. A., Bolton, D. C., Bendheim, P. E., Groth, D. F., & Glenner, G. G. (1983) Cell .35, 349-358.
26、Basler, K., Oesch, B., Scott, M., Westaway, D., Walchli, M., Groth, D. F., Mckinley, M. P., Prusiner, S. B., & Weissmann, C. (1986) Cell 46, 417-428.
27、Gasset, M., Baldwin, M. A., Lloyd, D., Gabriel, J. -M., Holtzman, D. M., Cohen. F., Fletterick, R. & Prusiner, S. B. (1992) Proc. Natl. Acad. Sci. USA, 89, 10940-10944.
28、Huang,Z., Gabriel, J.-M., Baldwin, M. A., Fletterick, R. J., Prusiner, S. B. & Cohen, F. E. (1994) Proc. Natl. Acad. Sci. USA, 91, 7139-7143.
29、Pan, K.-M., Baldwin, M., Nguyen, J., Gasset, M., Serban, A., Groth, D., Mehlhorn, I., Huang, Z., Fletterick,R. J., Cohen, F. E. & Prusiner, S. B. (1993) Proc. Natl. Acad. Sci. USA, 90, 10962-10966.
30、Pergami, P., Jaffe, H. & Safar, J. (1996) Anal. Biochem. 236, 63-73.
31、Prusiner, S. B. (1997) Science. 278, 245-251.
32、Telling, G. C., Scott, M., Mastrianni, J., Gabizon, Ruth., Torchia, M., Cohen, F. E., DeArmond, S. J. & Prusiner, S. B. (1995) Cell. 83, 79-90.
33、Kaneko, K., Zulianello, L., Scott, M., Cooper, C. M., Wallace, A. C., James, T. L., Cohen, F. E. & Prusiner, S. B. (1997) Proc. Natl. Acad. Sci. USA, 94, 10069-10074.
34、Hall, D. & Edskes, H. (2004) J. Mol. Biol. 336, 775-786
35、Prusiner, S. B, in Prion Biology and Diseases, edited by S.B. Prusiner (Cold spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999) p585-652.
36、Brown, P., Gibbs, C. J., Rodgers-Johnson, P., Asher, D. M., Sulima, M. P., Bacote, Alfred., Goldfarb, L. G. & Gajdusek, D. C. (1994) Ann. Neurol. 35, 513-529.
37、Tateishi, J., Kitamoto, T., Dohura, K., Sakaki, Y., Steinmetz, G., Tranchant, C., Warter, J. M. & Heldt, N. (1990) Neurology 40, 1578-1581.
38、Tateishi, J., Kitamoto, T., Hoque, M. Z. & Furukawa, H (1996) Neurology 46, 532-537.
39、Tateishi, J. & Kitamoto, T. (1995) Brain Path. 5, 53-59.
40、Hegde, R. S., Mastrianni, J. A., Scott, M. R., Defea, K. A., Tremblay, P., Torchia, M., DeArmond, S. J., Prusiner, S., & Lingappa, V. R. (1998) Science 279, 827-834.
41、Hegde, R. S., Tremblay, P., Groth, D., DeArmond, S. J., Prusiner, S. B. & Lingappa, V. R. (1999) Nature 402, 822-826.
42、Harris, D. A. (2003) British Medical Bulletin 66, 71-85.
43、Hall, D. & Edskes, H. (2004) J. Mol. Biol. 336, 775-786.
44、張聰民,蕭明裕,彭瓊琿,王文綺 編譯,生物化學。p.224. 2003年初版,新文京圖書發行
45、Bornberg-Bauer, E. & Chan, H. S. (1999) Proc. Natl. Acad. Sci. USA, 96, 10689-10694.
46、Bryngelson, J. D., Onuchic, J. N., Socci, N. D. & Wolynes, P. G. (1995) Proteins Struct. Funct. Genet. 21, 167-195.
47、Buchler, N. E. G. & Goldstein, R. A (1999) J. Che. Phys. 111, 6599-6609.
48、Chan, H. S. & Dill, K. A. (1991) J. Chem. Phys. 95, 3775-3787.
49、Chan, H. S. & Dill, K. A. (1994) J. Chem. Phys. 100, 9238-9257.
50、Dill, K. A. & Chan H. S. (1997) Nature Struc. Biol. 4, 10-19.
51、Dinner, A. R. & Karplus, M. (1999) J. Mol. Biol. 292, 403-419.
52、Govindarajan, S. & Goldsteinm, R. A. (1997) Proteins, Struct. Funct. Genet. 29, 461-466.
53、Klimov, D. K. & Thirumalaim D. (1996) Proteins, Struct. Funct. Genet. 26, 411-441.
54、Leopold, P. E., Montal, M. & Onuchic, J. N. (1992) Proc. Natl. Acad. Sci. USA, 89, 8721-8725.
55、Li, H., Helling, R., Tang, C, & Wingreen, N. (1996) Science 273, 666-669.
56、Pande, V. S. & Rokshar, D. S. (1999) Proc. Natl. Acad. Sci. USA, 96, 1273-1278.
57、Sali, A., Shakhnovich, E. I. & Karplus, M. (1994) Nature 369, 630-631.
58、Harrison, R. M., Chan, H. S., Prusiner, S. B. & Cohen, F. E. (2001) Protein Science 10, 819-835.
59、Dima, R. I & Thirumalai, D. (2002) Protein Science 11, 1036-1049.
60、Malolepsza, E., Boniecki, M., Kolinski, A. & Piela, L. (2005) Proc. Natl. Acad. Sci. USA, 102, 7835-7840.
61、Skolnick, J., Zhang, Y., Arakaki, A. K., Kolinski, A., Boniecki, M., Szilagyi, A. & Kihara, D. (2003) Proteins 53,Suppl. 6, 469-479.
62、Boniecki, M., Rotkiewicz, P., Skolinick, J. & Kolinski, A. (2003) J. Comput. Aided Mol. Des. 17, 725-738.
63、Swendsen, R. H. & Wang, J. S. (1986) Phys. Rev. Lett. 57, 2607-2609.
64、Sekijima, M., Motono, C., Yamasaki, S., Kaneko, K. & Akiyama, Y. (2003) Biophys. J. 85, 1176-1185.
65、Gu, W., Wang, T., Zhu, J., Shi, Y. & Liu, H. (2003) Biophys. Chem. 104, 79-94.
66、Ding, F., Dokholyan, N. V., Buldyrev, S. V., Stanley, H. E. & Shakhnovich, E. I. (2002) J. Mol. Biol. 324, 851-857.
67、Urbanc, B., Cruz, L., Ding, F., Sammond, D., Khare, S., Buldyrev, S. V., Stanley, H. E. & Dokholyan, N. V. (2004) Biophys. J. 87, 2310-2321.
68、DeMarco, M. L. & Daggett, V. (2004) Proc. Natl. Acad. Sci. USA, 101, 2293-2298.
69、Laurent, M. (1997) FEBS Letters 407, 1-6.
70、Prusiner, S. B. (1991) Science 252, 1515-1522.
71、Chen, C. –M. & Chen, C. –C. (2003) Biophys. J. 84, 1902-1908.
72、Chen, C. –M. (2001) Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 63, 010901
73、Metropolis, N. & Ulam, S. (1949) J. Amer. Stat. Assoc. 44, 335-341.
74、http://cern.ch/placzek Placzek, W. NFN and University of Pavia, 18–22 October 2004
75、Metropolis, N., Rosenbluth, A. W., Rosenbluth, M. N., Teller, A. H. & Teller, E. (1953) Journal of Chemical Physics 21, 1087-1092.
76、Carmensin, I & Kremer, K. (1988) Macromolecules 21, 2819-2823.
77、Donne, D.G., Viles, J. H., Groth, D., Mehlhorn, I., James, T. L., Cohen, F. E., Prusiner, S. B., Wright, P. E. & Dyson, H. J. (1997) Proc. Natl. Acad. Sci. USA, 94, 13452-13457.