跳到主要內容

臺灣博碩士論文加值系統

(44.222.104.206) 您好!臺灣時間:2024/05/28 01:12
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:林淑娟
研究生(外文):LIM, SUH CIUAN
論文名稱:The Alexander disease causing mutations of GFAP are deleterious to filament assembly and network formation
論文名稱(外文):亞力山大氏症GFAP基因突變對於中間型蛋白絲的聚合及形成絲狀纖維能力的影響
指導教授:彭明德彭明德引用關係
指導教授(外文):Perng, Ming-Der
口試委員:張壯榮李文權
口試日期:2011-7-21
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:英文
論文頁數:104
中文關鍵詞:神經膠質纖維酸性蛋白質突變亞力山大氏症中間型蛋白絲小分子量熱休克蛋白質磷酸化壓力
外文關鍵詞:GFAPmutationAlexander diaseaseintermediate filamentsmall heat shock proteinsphosphorylationstress
相關次數:
  • 被引用被引用:0
  • 點閱點閱:267
  • 評分評分:
  • 下載下載:3
  • 收藏至我的研究室書目清單書目收藏:0
亞力山大氏症(Alexander disease)是一種罕見且致命的中樞神經退化性疾病。目前發現這種疾病的發生與腦部星狀細胞(Astrocyte)的中間型蛋白絲(Intermediate filaments; IFs),即神經膠質纖維酸性蛋白質(glial fibrillary acidic protein; GFAP)的基因突變有關。亞力山大氏症的主要病理特徵是星狀細胞出現包含體,即所謂的Rosenthal fibers,內含GFAP及小分子量熱休克蛋白質(Small heat shock proteins; sHSPs)。引起亞力山大氏症的GFAP基因突變位置主要位於α-helical rod domain,亦有一部份突變點位在C端。本研究首先探討五種基因突變點位於C端的GFAP致病蛋白(N386I, S393I, N398F/Y和D417M14X) 如何影響中間型蛋白絲結構及聚合的能力以及干擾細胞內絲狀纖維的形成。結果顯示,這些C端具有基因突變的GFAP不但無法在in vitro聚合成正常的蛋白質絲狀纖維結構,亦會促使溶解度的改變而使蛋白質堆積,並引發大量sHSPs chaperone蛋白和αB-crystalline聚集,以及p38的磷酸化。此外,本研究也進一步探討R79C, R239H及Y366H這三種基因突變點位於α-helical rod domain的GFAP致病蛋白,它們可能引發壓力反應(stress response)的一些相關機制。結果發現這些GFAP致病蛋白能磷酸化壓力活化蛋白質激酶 (Jun N-terminal kinase; JNK/ stress activated protein kinases; SAPK),使JNK3和 p53的表現量增加並活化caspase 3。以上研究結果顯示,突變型GFAP可藉由致病蛋白質的堆積,chaperone蛋白的封存和壓力反應(相關機制包括p38與JNK的磷酸化;增加JNK與p53的表現量以及活化caspase 3),而影響中間型蛋白絲的聚合及形成絲狀纖維能力,並可作為探討亞力山大氏症相關致病機轉關鍵線索。

關鍵字:神經膠質纖維酸性蛋白質,突變,亞力山大氏症,中間型蛋白絲,小分子量熱休克蛋白質,磷酸化,壓力

Alexander disease (AxD) is a rare, fatal neurodegenerative disorder caused by dominant mutations in the astrocyte-specific intermediate filament (IF) glial fibrillary acidic protein (GFAP). The pathological feature AxD is the abundant presence of Rosenthal fibers, the ubiquitinated protein inclusions within cytoplasm of astrocytes containing GFAP, the small heat shock proteins (sHSPs) αB-crystallin and HSP27. Although most disease-causing mutations are found in the α-helical rod domain of GFAP, some mutations are also found in the C-terminal tail domain. This study aimed to clarify how C-terminal mutations (N386I, S393I, N398F/Y and D417M14X) affect GFAP filament assembly in vitro and filament network organization in cells. Results showed that these mutations disrupted in vitro assembly, promoted aggregation by solubility alteration, encouraged the association of small heat shock proteins (sHSPs) chaperone, αB-crystalline and phosphorylation of p38. For further investigation, three GFAP α-helical rod domain mutations, R79C, R239H and Y366H were additionally involved for the possible stress-induced mechanism of expressing GFAP mutants. Their abilities of induce stress activated protein kinases (SAPK) Jun N-terminal kinase (JNK) phosphorylation, activation of JNK 3, p53 and caspase 3 have been demonstrated in this study. Collectively, these data confirm that the GFAP mutations affect filament assembly in a way that promotes aggregate formation, chaperone sequestration, p38 and JNK phosphorylation and increasing expression level of JNK, p53 and caspase 3, suggesting these are the key to the mechanism(s) underlying the AxD.

Keywords: GFAP, mutation, Alexander disease, intermediate filament, small heat shock proteins, phosphorylation, stress

Contents
Abstract……………………………………………………………I
摘要…………………………………………………………………II
致謝…………………………………………………………………III
Abbreviations………………………………………………………IV
1 Introduction…………………………………………………1
1.1 The astrocyte intermediatefilaments…………………1
1.2 GFAP function and expression……………………………3
1.3 Alexander disease and GFAP mutation……………………4
1.4 Model system for AxD study………………………………10
1.5 Outline of study……………………………………………12
2 Materials and methods………………………………………14
2.1 Plasmid construction and site-directed mutagenesis…14
2.2 Expression and purification of recombinant GFAPs……14
2.3 In vitro assembly and sedimentation assay………………16
2.4 Electron microscopy……………………………………………17
2.5 Gel-electrophoresis—SDS PAGE………………………………18
2.6 Cell cultures……………………………………………………18
2.7 Cell transient transfection and treatments……………18
2.8 Immmunofluoresence microscopy………………………………19
2.9 Cellular fractionation…………………………………………20
2.10 Immunoblotting…………………………………………………21
3 Results………………………………………………………………23
3.1 GFAP mutation constructs, expression and purification…………………………………………………………23
3.2 Effects of GFAP mutations on in vitro GFAP assembly…24
3.3 Effects of GFAP mutations upon GFAP network in cells lacking endogenous GFAP……………………………………………25
3.4 The alteration of the binding properties of GA5 antibody to GFAP……………………………………………………27
3.5 Assembly properties of mutant GFAP in human astrocytoma cells expressed endogenous GFAP…………………………………29
3.6 The mutant GFAP induce Rosenthal fibers similar aggregates and stress response…………………………………30
4 Discussion…………………………………………………………35
4.1 GFAP tail mutations affects IF assembly, interaction and network organization…………………………………………35
4.2 The possible contribution of mutant GFAP to mitochondrial dysfunction…………………………………………36
4.3 Association of αB-crystallin and Hsp27 with mutant GFAP aggregates………………………………………………………38
4.4 Accumulation of mutant GFAP induce stress response and abnormal protein degradation……………………………………………………………39
4.5 Further prospects………………………………………………43
References……………………………………………………………45
Figures…………………………………………………………………55
Figure 1. A schematic diagram of a GFAP structure and the mutations involved in this study………………………………55
Figure 2. The GFAP mutant constructs…………………………56
Figure 3. Expression purification and electrophoretic analysis of WT and mutant GFAPs…………………………………59
Figure 4. GFAP tail mutations affect in vitro filament assembly…………………………………………………………………62
Figure 5. Effects of GFAP tail mutations upon the IF network formation……………………………………………………64
Figure 6. Analysis and the expression of wild type and GFAP tail mutations in SW13/cl.1 (Vim+) cells………………65
Figure 7. Epitope mapping of a monoclonal antibody GA5 binding site on GFAP…………………………………………………67
Figure 8. Filament organization properties of WT and mutant GFAPs in astrocytoma U343MG cells………………………………69
Figure 9. GFAP aggregates disrupt endogenous IF
networks…………………………………………………………………70
Figure 10. Activation of p38 kinase and associations with sHSPs by mutant GFAPs in transfected U343MG cells…………71
Figure 11. Increase expression of p53 and phosphorylation of JNK by mutant GFAPs in transfected U343MG cells…………73
Figure 12. Activation of caspase-3 and increasing JNK3 expression by mutant GFAPs in transfected U343MG cells……76
Figure 13. The expression of heat-shock proteins in wild type and GFAP rod domain mutations transfected U343MG cells……………………………………………………………………78
Appendix…………………………………………………………………81
Appendix 1. Gel component…………………………………………81
Appendix 2. GFAP mutants associated with AxD…………………82
Appendix 3. Alexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability network formation …90

[1] Acarin, L., Villapol, S., Faiz, M., Rohn, T.T., Castellano, B., and Gonzalez, B. (2007). Caspase-3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation. Glia 55, 954-965.
[2] Alexander, W.S. (1949). Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 72, 373-381.
[3] Antoniou, X., Falconi, M., Di Marino, D., and Borsello, T. (2011). JNK3 as a therapeutic target for neurodegenerative diseases. J Alzheimers Dis, 24, 633-642.
[4] Arrigo, A.P., Simon, S., Gibert, B., Kretz-Remy, C., Nivon, M., Czekalla, A., Guillet, D., Moulin, M., Diaz-Latoud, C., and Vicart, P. (2007). Hsp27 (HspB1) and alpha B-crystallin (HspB5) as therapeutic targets. Febs Letters 581, 3665-3674.
[5] Avila, J. (2010). Alzheimer disease: caspases first. Nat Rev Neurol 6, 587-588.
[6] Bär, H., Schopferer, M., Sharma, S., Hochstein, B., Mücke, N., Herrmann, H., and Willenbacher, N. (2010). Mutations in desmin's carboxy-terminal “tail” domain severely modify filament and network mechanics. Journal of Molecular Biology 397, 1188-1198.
[7] Bar, H., Goudeau, B., Walde, S., Casteras-Simon, M., Mucke, N., Shatunov, A., Goldberg, Y.P., Clarke, C., Holton, J.L., Eymard, B., et al. (2007). Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies. Hum Mutat 28, 374-386.
[8] Beal, M.F. (2005). Mitochondria take center stage in aging and neurodegeneration. Annals of Neurology 58, 495-505.
[9] Becker, L.E., Teixeira, F. (1988). Alexander's disease. In MDNorenberg, L Hertz, & A Schousboe (Eds), The Biochemical Pathology of Astrocytes, 179-190.
[10] Bernot, K.M., Lee, C.H., and Coulombe, P.A. (2005). A small surface hydrophobic stripe in the coiled-coil domain of type I keratins mediates tetramer stability. Journal of Cell Biology 168, 965-974.
[11] Boatright, K.M., and Salvesen, G.S. (2003). Mechanisms of caspase activation. Curr Opin Cell Biol 15, 725-731.
[12] Boelens, W.C., Croes, Y., and de Jong, W.W. (2001). Interaction between alpha B-crystallin and the human 20S proteasomal subunit C8/alpha 7. Bba-Protein Struct M 1544, 311-319.
[13] Bongcam-Rudloff, E., Nister, M., Betsholtz, C., Wang, J.L., Stenman, G., Huebner, K., Croce, C.M., and Westermark, B. (1991). Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes. Cancer Res 51, 1553-1560.
[14] Bonne, G., Di Barletta, M.R., Varnous, S., Becane, H.M., Hammouda, E.H., Merlini, L., Muntoni, F., Greenberg, C.R., Gary, F., Urtizberea, J.A., et al. (1999). Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nature Genetics 21, 285-288.
[15] Borsello, T., Clarke, P.G., Hirt, L., Vercelli, A., Repici, M., Schorderet, D.F., Bogousslavsky, J., and Bonny, C. (2003). A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9, 1180-1186.
[16] Bramanti, V., Tomassoni, D., Avitabile, M., Amenta, F., and Avola, R. (2010). Biomarkers of glial cell proliferation and differentiation in culture. Front Biosci (Schol Ed) 2, 558-570.
[17] Brecht, S., Kirchhof, R., Chromik, A., Willesen, M., Nicolaus, T., Raivich, G., Wessig, J., Waetzig, V., Goetz, M., Claussen, M., et al. (2005). Specific pathophysiological functions of JNK isoforms in the brain. European Journal of Neuroscience 21, 363-377.
[18] Brenner, M., Johnson, A.B., Boespflug-Tanguy, O., Rodriguez, D., Goldman, J.E., and Messing, A. (2001). Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27, 117-120.
[19] Brenner, M., Kisseberth, W.C., Su, Y., Besnard, F., and Messing, A. (1994). Gfap promoter directs astrocyte-specific expression in transgenic mice. Journal of Neuroscience 14, 1030-1037.
[20] Brenner, M., Lampel, K., Nakatani, Y., Mill, J., Banner, C., Mearow, K., Dohadwala, M., Lipsky, R., and Freese, E. (1990). Characterization of human cdna and genomic clones for glial fibrillary acidic protein. Mol Brain Res 7, 277-286.
[21] Caceres-Marzal, C., Vaquerizo, J., Galan, E., and Fernandez, S. (2006). Early mitochondrial dysfunction in an infant with Alexander disease. Pediatr Neurol 35, 293-296.
[22] Carotti, S., Morini, S., Corradini, S.G., Burza, M.A., Molinaro, A., Carpino, G., Merli, M., De Santis, A., Muda, A.O., Rossi, M., et al. (2008). Glial fibrillary acidic protein as an early marker of hepatic stellate cell activation in chronic and posttransplant recurrent hepatitis C. Liver Transplant 14, 806-814.
[23] Castellani, R.J., Perry, G., Harris, P.L.R., Cohen, M.L., Sayre, L.M., Salomon, R.G., and Smith, M.A. (1998). Advanced lipid peroxidation end-products in Alexander's disease. Brain Res 787, 15-18.
[24] Chen, W.J., and Liem, R.K.H. (1994). The endless story of the glial fibrillary acidic protein. Journal of Cell Science 107, 2299-2311.
[25] Coulombe, P.A., Hutton, M.E., Letai, A., Hebert, A., Paller, A.S., and Fuchs, E. (1991). Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell 66, 1301-1311.
[26] D'Alessandro, M., Russell, D., Morley, S.M., Davies, A.M., and Lane, E.B. (2002). Keratin mutations of epidermolysis bullosa simplex alter the kinetics of stress response to osmotic shock. Journal of Cell Science 115, 4341-4351.
[27] Debus, E., Weber, K., and Osborn, M. (1983). Monoclonal antibodies specific for glial fibrillary acidic protein (GFAP) and for each of the neurofilament triplet polypeptides. Differentiation 25, 193-203.
[28] den Engelsman, J., Keijsers, V., de Jong, W.W., and Boelens, W.C. (2003). The small heat-shock protein alpha B-crystallin promotes FBX4-dependent ubiquitination. Journal of Biological Chemistry 278, 4699-4704.
[29] Der Perng, M., Su, M., Wen, S.F., Li, R., Gibbon, T., Prescott, A.R., Brenner, M., and Quinlan, R.A. (2006). The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27. Am J Hum Genet 79, 197-213.
[30] Duffy, L.M., Chapman, A.L., Shaw, P.J., and Grierson, A.J. (2011). Review: The role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 37, 336-352.
[31] Eddleston, M., and Mucke, L. (1993). Molecular profile of reactive astrocytes - implications for their role in neurologic disease. Neuroscience 54, 15-36.
[32] Eliasson, C., Sahlgren, C., Berthold, C.H., Stakeberg, J., Celis, J.E., Betsholtz, C., Eriksson, J.E., and Pekny, M. (1999). Intermediate filament protein partnership in astrocytes. J Biol Chem 274, 23996-24006.
[33] Eng, L.F., Ghirnikar, R.S., and Lee, Y.L. (2000). Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 25, 1439-1451.
[34] Eng, L.F., Lee, Y.L., Kwan, H., Brenner, M., and Messing, A. (1998). Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain Rosenthal fibers. J Neurosci Res 53, 353-360.
[35] Eng, L.F., Vandenha.Jj, Bignami, A., and Gerstl, B. (1971). Acidic protein isolated from fibrous astrocytes. Brain Res 28, 351-354.
[36] Engel, R.H., and Evens, A.M. (2006). Oxidative stress and apoptosis: a new treatment paradigm in cancer. Front Biosci 11, 300-312.
[37] Farina, L., Pareyson, D., Minati, L., Ceccherini, I., Chiapparini, L., Romano, S., Gambaro, P., Fancellu, R., and Savoiardo, M. (2008). Can MR imaging diagnose adult-onset Alexander disease? Am J Neuroradiol 29, 1190-1196.
[38] Garcia, M., Vanhoutte, P., Pages, C., Besson, M.J., Brouillet, E., and Caboche, J. (2002). The mitochondrial toxin 3-nitropropionic acid induces striatal neurodegeneration via a c-Jun N-terminal kinase/c-Jun module. J Neurosci 22, 2174-2184.
[39] Geng, Y., Walls, K.C., Ghosh, A.P., Akhtar, R.S., Klocke, B.J., and Roth, K.A. (2010). Cytoplasmic p53 and activated Bax regulate p53-dependent, transcription-independent neural precursor cell apoptosis. Journal of Histochemistry & Cytochemistry 58, 265-275.
[40] Goldman, J.E., Tang, G.M., and Xu, Z.H. (2006). Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease. Journal of Biological Chemistry 281, 38634-38643.
[41] Gomi, H., Yokoyama, T., and Itohara, S. (2010). Role of GFAP in morphological retention and distribution of reactive astrocytes induced by scrapie encephalopathy in mice. Brain Res 1312, 156-167.
[42] Hagemann, T.L., Boelens, W.C., Wawrousek, E.F., and Messing, A. (2009). Suppression of GFAP toxicity by alpha B-crystallin in mouse models of Alexander disease. Human Molecular Genetics 18, 1190-1199.
[43] Hagemann, T.L., Connor, J.X., and Messing, A. (2006). Alexander disease-associated glial fibrillary acidic protein mutations in mice induce Rosenthal fiber formation and a white matter stress response. J Neurosci 26, 11162-11173.
[44] Hagemann, T.L., Gaeta, S.A., Smith, M.A., Johnson, D.A., Johnson, J.A., and Messing, A. (2005). Gene expression analysis in mice with elevated glial fibrillary acidic protein and Rosenthal fibers reveals a stress response followed by glial activation and neuronal dysfunction. Hum Mol Genet 14, 2443-2458.
[45] Hainfellner, J.A., Voigtlander, T., Strobel, T., Mazal, P.R., Maddalena, A.S., Aguzzi, A., and Budka, H. (2001). Fibroblasts can express glial fibrillary acidic protein (GFAP) in vivo. J Neuropath Exp Neur 60, 449-461.
[46] Hansson, E., and Ronnback, L. (1995). Astrocytes in glutamate neurotransmission. FASEB J 9, 343-350.
[47] Head, M.W., Corbin, E., and Goldman, J.E. (1993). Overexpression and abnormal modification of the stress proteins alpha-B-Crystallin and Hsp27 in Alexander-Disease. American Journal of Pathology 143, 1743-1753.
[48] Hedberg, K.K., and Chen, L.B. (1986). Absence of intermediate filaments in a human adrenal cortex carcinoma-derived cell line. Exp Cell Res 163, 509-517.
[49] Herrmann, H., and Aebi, U. (2000). Intermediate filaments and their associates: multi-talented structural elements specifying cytoarchitecture and cytodynamics. Curr Opin Cell Biol 12, 79-90.
[50] Herrmann, H., and Aebi, U. (2004). Intermediate filaments: Molecular structure, assembly mechanism, and integration into functionally distinct intracellular scaffolds. Annu Rev Biochem 73, 749-789.
[51] Herrmann, H., Bar, H., Goudeau, B., Walde, S., Casteras-Simon, M., Mucke, N., Shatunov, A., Goldberg, Y.P., Clarke, C., Holton, J.L., et al. (2007). Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies. Human Mutation 28, 374-386.
[52] Hsiao, V.C., Tian, R., Long, H., Perng, M.D., Brenner, M., Quinlan, R.A., and Goldman, J.E. (2005). Alexander-disease mutation of GFAP causes filament disorganization and decreased solubility of GFAP. Journal of Cell Science 118, 2057-2065.
[53] Ishigaki, K., Ito, Y., Sawaishi, Y., Kodaira, K., Funatsuka, M., Hattori, N., Nakano, K., Saito, K., and Osawa, M. (2006). TRH therapy in a patient with juvenile Alexander disease. Brain Dev 28, 663-667.
[54] Iwaki, T., Iwaki, A., Tateishi, J., Sakaki, Y., and Goldman, J.E. (1993). Alpha-B-crystallin and 27-Kd heat-shock protein are regulated by stress conditions in the central-nervous-system and accumulate in Rosenthal fibers. American Journal of Pathology 143, 487-495.
[55] Iwaki, T., Kumeiwaki, A., Liem, R.K.H., and Goldman, J.E. (1989). Alpha-B-crystallin is expressed in non-lenticular tissues and accumulates in Alexanders disease brain. Cell 57, 71-78.
[56] Johnson, A.B., (1996). Alexander disease. In: Moser HW, editor Neurodystrophies and neurolipidoses Handbook of clinical neurology Vol. 66 (revised series Vol. 22), 701-710.
[57] Johnson, A.B., and Bettica, A. (1989). On-grid immunogold labeling of glial intermediate filaments in epoxy-embedded tissue. Am J Anat 185, 335-341.
[58] Kalman, M., and Ajtai, B.M. (2001). A comparison of intermediate filament markers for presumptive astroglia in the developing rat neocortex: immunostaining against nestin reveals more detail, than GFAP or vimentin. International Journal of Developmental Neuroscience 19, 101-108.
[59] Kim, Y.J., Yi, Y., Sapp, E., Wang, Y., Cuiffo, B., Kegel, K.B., Qin, Z.H., Aronin, N., and DiFiglia, M. (2001). Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci U S A 98, 12784-12789.
[60] King, R.J., Finley, J.R., Coffer, A.I., Millis, R.R., and Rubens, R.D. (1987). Characterization and biological relevance of a 29-kDa, oestrogen receptor-related protein. J Steroid Biochem 27, 471-475.
[61] Koyama, Y., and Goldman, J.E. (1999). Formation of GFAP cytoplasmic inclusions in astrocytes and their disaggregation by alpha B-crystallin. American Journal of Pathology 154, 1563-1572.
[62] Ku, N.O., and Omary, M.B. (2006). A disease- and phosphorylation-related nonmechanical function for keratin 8. Journal of Cell Biology 174, 115-125.
[63] Kuan, C.Y., Whitmarsh, A.J., Yang, D.D., Liao, G., Schloemer, A.J., Dong, C., Bao, J., Banasiak, K.J., Haddad, G.G., Flavell, R.A., et al. (2003). A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci U S A 100, 15184-15189.
[64] Laemmli, U.K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-685.
[65] Laywell, E.D., Rakic, P., Kukekov, V.G., Holland, E.C., and Steindler, D.A. (2000). Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci U S A 97, 13883-13888.
[66] Lepekhin, E.A., Eliasson, C., Berthold, C.H., Berezin, V., Bock, E., and Pekny, M. (2001). Intermediate filaments regulate astrocyte motility. Journal of Neurochemistry 79, 617-625.
[67] Li, H., Guo, Y., Teng, J., Ding, M., Yu, A.C., and Chen, J. (2006). 14-3-3gamma affects dynamics and integrity of glial filaments by binding to phosphorylated GFAP. J Cell Sci 119, 4452-4461.
[68] Li, R., Johnson, A.B., Salomons, G., Goldman, J.E., Naidu, S., Quinlan, R., Cree, B., Ruyle, S.Z., Banwell, B., D'Hooghe, M., et al. (2005). Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 57, 310-326.
[69] Liedtke, W., Edelmann, W., Bieri, P.L., Chiu, F.C., Cowan, N.J., Kucherlapati, R., and Raine, C.S. (1996). GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron 17, 607-615.
[70] Maloyan, A., Osinska, H., Lammerding, J., Lee, R.T., Cingolani, O.H., Kass, D.A., Lorenz, J.N., and Robbins, J. (2009). Biochemical and mechanical dysfunction in a mouse model of desmin-related myopathy. Circulation Research 104, 1021-1028.
[71] McCall, M., Gregg, R., Behringer, R.R., Brenner, M., Zheng, C.L., Pearce, R.A., Chiu, S.Y., Delaney, C.L., and Messing, A. (1996). Targeted deletion in astrocyte intermediate filament (GFAP) alters neuronal physiology. Journal of Neurochemistry 66, S75-S75.
[72] Mccormick, M.B., Kouklis, P., Syder, A., and Fuchs, E. (1993). The roles of the rod end and the tail in vimentin If-assembly and If-network formation. Journal of Cell Biology 122, 395-407.
[73] McLean, W.H.I., Smith, F.J.D., and Cassidy, A.J. (2005). Insights into genotype-phenotype correlation in pachyonychia congenita from the human intermediate filament mutation database. J Invest Derm Symp P 10, 31-36.
[74] Meisingset, T.W., Risa, O., Brenner, M., Messing, A., and Sonnewald, U. (2010). Alteration of glial-neuronal metabolic interactions in a mouse model of Alexander disease. Glia 58, 1228-1234.
[75] Meriin, A.B., Mabuchi, K., Gabai, V.L., Yaglom, J.A., Kazantsev, A., and Sherman, M.Y. (2001). Intracellular aggregation of polypeptides with expanded polyglutamine domain is stimulated by stress-activated kinase MEKK1. J Cell Biol 153, 851-864.
[76] Messing, A., Head, M.W., Galles, K., Galbreath, E.J., Goldman, J.E., and Brenner, M. (1998). Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. American Journal of Pathology 152, 391-398.
[77] Mignot, C., Boespflug-Tanguy, O., Gelot, A., Dautigny, A., Pham-Dinh, D., and Rodriguez, D. (2004). Alexander disease: putative mechanisms of an astrocytic encephalopathy. Cellular and Molecular Life Sciences 61, 369-385.
[78] Morgan, T.E., Rozovsky, I., Goldsmith, S.K., Stone, D.J., Yoshida, T., and Finch, C.E. (1997). Increased transcription of the astrocyte gene GFAP during middle-age is attenuated by food restriction: Implications for the role of oxidative stress. Free Radical Bio Med 23, 524-528.
[79] Mouser, P.E., Head, E., Ha, K.H., and Rohn, T.T. (2006). Caspase-mediated cleavage of glial fibrillary acidic protein within degenerating astrocytes of the Alzheimer's disease brain. Am J Pathol 168, 936-946.
[80] Murakami, N., Tsuchiya, T., Kanazawa, N., Tsujino, S., and Nagai, T. (2008). Novel deletion mutation in GFAP gene in an infantile form of Alexander disease. Pediatr Neurol 38, 50-52.
[81] Nicholl, I.D., and Quinlan, R.A. (1994). Chaperone activity of alpha-crystallins modulates intermediate filament assembly. Embo Journal 13, 945-953.
[82] Nicolet, S., Herrmann, H., Aebi, U., and Strelkov, S.V. (2010). Atomic structure of vimentin coil 2. Journal of Structural Biology 170, 369-376.
[83] Nobuhara, Y., Nakahara, K., Higuchi, I., Yoshida, T., Fushiki, S., Osame, M., Arimura, K., and Nakagawa, M. (2004). Juvenile form of Alexander disease with GFAP mutation and mitochondrial abnormality. Neurology 63, 1302-1304.
[84] Omary, M.B., Coulombe, P.A., and McLean, W.H.I. (2004). Mechanisms of disease: Intermediate filament proteins and their associated diseases. New Engl J Med 351, 2087-2100.
[85] Omary, M.B., Ku, N.O., Tao, G.Z., Toivola, D.M., and Liao, J. (2006). 'Heads and tails' of intermediate filament phosphorylation: multiple sites and functional insights. Trends in Biochemical Sciences 31, 383-394.
[86] Ozben, T. (2007). Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci 96, 2181-2196.
[87] Pareyson, D., Fancellu, R., Mariotti, C., Romano, S., Salmaggi, A., Carella, F., Girotti, F., Gattellaro, G., Carriero, M.R., Farina, L., et al. (2008). Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature. Brain 131, 2321-2331.
[88] Parry, D.A.D. (2005). Microdissection of the sequence and structure of intermediate filament chains. Adv Protein Chem 70, 113-142.
[89] Parry, D.A.D., Strelkov, S.V., Burkhard, P., Aebi, U., and Herrmann, H. (2007). Towards a molecular description of intermediate filament structure and assembly. Experimental Cell Research 313, 2204-2216.
[90] Pegram, C.N., Eng, L.F., Wikstrand, C.J., McComb, R.D., Lee, Y.L., and Bigner, D.D. (1985). Monoclonal antibodies reactive with epitopes restricted to glial fibrillary acidic proteins of several species. Neurochem Pathol 3, 119-138.
[91] Pekny, M., Leveen, P., Pekna, M., Eliasson, C., Berthold, C.H., Westermark, B., and Betsholtz, C. (1995). Mice lacking glial fibrillary acidic protein display astrocytes devoid of intermediate filaments but develop and reproduce normally. Embo Journal 14, 1590-1598.
[92] Perng, M.D., Cairns, L., van den, I.P., Prescott, A., Hutcheson, A.M., and Quinlan, R.A. (1999). Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin. J Cell Sci 112 ( Pt 13), 2099-2112.
[93] Perng, M.D., Wen, S.F., Gibbon, T., Middeldorp, J., Sluijs, J., Hol, E.M., and Quinlan, R.A. (2008). Glial fibrillary acidic protein filaments can tolerate the incorporation of assembly-compromised GFAP-delta , but with consequences for filament organization and alpha B-Crystallin association. Molecular Biology of the Cell 19, 4521-4533.
[94] Perng, M.D., Wen, S.F., van den Ijssel, P., Prescott, A.R., and Quinlan, R.A. (2004). Desmin aggregate formation by R120G alpha B-crystallin is caused by altered filament interactions and is dependent upon network status in cells. Molecular Biology of the Cell 15, 2335-2346.
[95] Pietenpol, J., and Vogelstein, B. (1994). P53 function and dysfunction. Journal of Cellular Biochemistry, 163-163.
Pollard, T.D., and Cooper, J.A. (1982). Methods to characterize actin filament networks. Method Enzymol 85, 211-233.
[96] Privat, A. (2003). Astrocytes as support for axonal regeneration in the central nervous system of mammals. Glia 43, 91-93.
[97] Quinlan, R.A., Brenner, M., Goldman, J.E., and Messing, A. (2007). GFAP and its role in Alexander disease. Experimental Cell Research 313, 2077-2087.
[98] Quinlan, R.A., Moir, R.D., and Stewart, M. (1989). Expression in Escherichia coli of fragments of glial fibrillary acidic protein: characterization, assembly properties and paracrystal formation. J Cell Sci 93 ( Pt 1), 71-83.
[99] Riol, H., Tardy, M., Rolland, B., Levesque, G., and Murthy, M.R. (1997). Detection of the peripheral nervous system (PNS)-type glial fibrillary acidic protein (GFAP) and its mRNA in human lymphocytes. J Neurosci Res 48, 53-62.
[100] Roelofs, R.F., Fischer, D.F., Houtman, S.H., Sluijs, J.A., Van Haren, W., Van Leeuwen, F.W., and Hol, E.M. (2005). Adult human subventricular, subgranular, and subpial zones contain astrocytes with a specialized intermediate filament cytoskeleton. Glia 52, 289-300.
[101] Russo, L.S., Jr., Aron, A., and Anderson, P.J. (1976). Alexander's disease: a report and reappraisal. Neurology 26, 607-614.
[102] Rutka, J.T., Ivanchuk, S., Mondal, S., Taylor, M., Sakai, K., Dirks, P., Jun, P., Jung, S., Becker, L.E., and Ackerley, C. (1999). Co-expression of nestin and vimentin intermediate filaments in invasive human astrocytoma cells. Int J Dev Neurosci 17, 503-515.
[103] Salmaggi, A., Botturi, A., Lamperti, E., Grisoli, M., Fischetto, R., Ceccherini, I., Caroli, F., and Boiardi, A. (2007). A novel mutation in the GFAP gene in a familial adult onset Alexander disease. J Neurol 254, 1278-1280.
[104] Salvi, F., Aoki, Y., Della Nave, R., Vella, A., Pastorelli, F., Scaglione, C., Matsubara, Y., and Mascalchi, M. (2005). Adult Alexander's disease without leukoencephalopathy. Annals of Neurology 58, 813-814.
[105] Sandilands, A., Prescott, A.R., Carter, J.M., Hutcheson, A.N., Quinlan, R.A., Richards, J., and Fitzgerald, P.G. (1995). Vimentin and Cp49 filensin form distinct networks in the lens which are independently modulated during lens fiber cell-differentiation. J Cell Sci 108, 1397-1406.
[106] Santos, R.X., Correia, S.C., Wang, X., Perry, G., Smith, M.A., Moreira, P.I., and Zhu, X. (2010). Alzheimer's disease: diverse aspects of mitochondrial malfunctioning. Int J Clin Exp Pathol 3, 570-581.
[107] Sawada, K., Agata, K., Yoshiki, A., and Eguchi, G. (1993). A set of anti-crystallin monoclonal antibodies for detecting lens specificities: beta-crystallin as a specific marker for detecting lentoidogenesis in cultures of chicken lens epithelial cells. Jpn J Ophthalmol 37, 355-368.
[108] Schuler, M., Bossy-Wetzel, E., Goldstein, J.C., Fitzgerald, P., and Green, D.R. (2000). p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J Biol Chem 275, 7337-7342.
[109] Schweitzer, S.C., Klymkowsky, M.W., Bellin, R.M., Robson, R.M., Capetanaki, Y., and Evans, R.M. (2001). Paranemin and the organization of desmin filament networks. J Cell Sci 114, 1079-1089.
[110] Shen, Y., and White, E. (2001). p53-dependent apoptosis pathways. Adv Cancer Res 82, 55-84.
[111] Shibuki, K., Gomi, H., Chen, L., Bao, S., Kim, J.J., Wakatsuki, H., Fujisaki, T., Fujimoto, K., Katoh, A., Ikeda, T., et al. (1996). Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice. Neuron 16, 587-599.
[112] Sihag, R.K., Inagaki, M., Yamaguchi, T., Shea, T.B., and Pant, H.C. (2007). Role of phosphorylation on the structural dynamics and function of types III and IV intermediate filaments. Experimental Cell Research 313, 2098-2109.
[113] Song, S.H., Stevens, C.F., and Gage, F.H. (2002). Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39-44.
[114] Springer, S., Erlewein, R., Naegele, T., Becker, I., Auer, D., Grodd, W., and Krageloh-Mann, I. (2000). Alexander disease - Classification revisited and isolation of a neonatal form. Neuropediatrics 31, 86-92.
[115] Steinert, P.M., Chou, Y.H., Prahlad, V., Parry, D.A., Marekov, L.N., Wu, K.C., Jang, S.I., and Goldman, R.D. (1999). A high molecular weight intermediate filament-associated protein in BHK-21 cells is nestin, a type VI intermediate filament protein. Limited co-assembly in vitro to form heteropolymers with type III vimentin and type IV alpha-internexin. J Biol Chem 274, 9881-9890.
[116] Strelkov, S.V., Herrmann, H., Geisler, N., Wedig, T., Zimbelmann, R., Aebi, U., and Burkhard, P. (2002). Conserved segments 1A and 2B of the intermediate filament dimer: their atomic structures and role in filament assembly. Embo Journal 21, 1255-1266.
[117] Su, J.H., Kesslak, J.P., Head, E., and Cotman, C.W. (2002). Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain. Acta Neuropathol 104, 1-6.
[118] Sultana, S., Sernett, S.W., Bellin, R.M., Robson, R.M., and Skalli, O. (2000). Intermediate filament protein synemin is transiently expressed in a subset of astrocytes during development. Glia 30, 143-153.
[119] Szeverenyi, I., Cassidy, A.J., Chung, C.W., Lee, B.T., Common, J.E.A., Ogg, S.C., Chen, H., Sim, S.Y., Goh, W.L.R., Ng, K.W., et al. (2008). The human intermediate filament database: Comprehensive information on a gene family involved in many human diseases. Human Mutation 29, 351-360.
[120] Takemura, M., Gomi, H., Colucci-Guyon, E., and Itohara, S. (2002). Protective role of phosphorylation in turnover of glial fibrillary acidic protein in mice. Journal of Neuroscience 22, 6972-6979.
[121] Takizawa, T., Gudla, P.R., Guo, L.Y., Lockett, S., and Misteli, T. (2008). Allele-specific nuclear positioning of the monoallelically expressed astrocyte marker GFAP. Gene Dev 22, 489-498.
[122] Tang, G., Perng, M.D., Wilk, S., Quinlan, R., and Goldman, J.E. (2010). Oligomers of mutant glial fibrillary acidic protein (GFAP) Inhibit the proteasome system in Alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition. J Biol Chem 285, 10527-10537.
[123] Tang, G., Xu, Z., and Goldman, J.E. (2006). Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease. J Biol Chem 281, 38634-38643.
[124] Tang, G., Yue, Z., Talloczy, Z., Hagemann, T., Cho, W., Messing, A., Sulzer, D.L., and Goldman, J.E. (2008). Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways. Hum Mol Genet 17, 1540-1555.
[125] Tian, R.J., Gregor, M., Wiche, G., and Goldman, J.E. (2006). Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease. American Journal of Pathology 168, 888-897.
[126] Tomokane, N., Iwaki, T., Tateishi, J., Iwaki, A., and Goldman, J.E. (1991). Rosenthal fibers share epitopes with alpha-B-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin - Immunoelectron Microscopy with Colloidal Gold. American Journal of Pathology 138, 875-885.
[127] Tsujimura, K., Tanaka, J., Ando, S., Matsuoka, Y., Kusubata, M., Sugiura, H., Yamauchi, T., and Inagaki, M. (1994). Identification of phosphorylation sites on glial fibrillary acidic protein for cdc2 kinase and Ca2+-calmodulin-dependent protein-kinase-II. J Biochem-Tokyo 116, 426-434.
[128] van den, I.P., Norman, D.G., and Quinlan, R.A. (1999). Molecular chaperones: small heat shock proteins in the limelight. Curr Biol 9, R103-105.
[129] van der Knaap, M.S., Ramesh, V., Schiffmann, R., Blaser, S., Kyllerman, M., Gholkar, A., Ellison, D.W., van der Voorn, J.P., van Dooren, S.J., Jakobs, C., et al. (2006). Alexander disease: ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 66, 494-498.
[130] Verstraeten, V.L.R.M., Caputo, S., van Steensel, M.A.M., Duband-Goulet, I., Zinn-Justin, S., Kamps, M., Kuijpers, H.J.H., Ostlund, C., Worman, H.J., Briede, J.J., et al. (2009). The R439C mutation in LMNA causes lamin oligomerization and susceptibility to oxidative stress. J Cell Mol Med 13, 959-971.
[131] Wang, L., Colodner, K.J., and Feany, M.B. (2011). Protein misfolding and oxidative stress promote glial-mediated neurodegeneration in an Alexander disease model. J Neurosci 31, 2868-2877.
[132] Welsh, M.J., and Gaestel, M. (1998). Small heat-shock protein family: Function in health and disease. Stress of Life 851, 28-35.
[133] Wu, K.C., Bryan, J.T., Morasso, M.I., Jang, S.I., Lee, J.H., Yang, J.M., Marekov, L.N., Parry, D.A.D., and Steinert, P.M. (2000). Coiled-coil trigger motifs in the 1B and 2B rod domain segments are required for the stability of keratin intermediate filaments. Molecular Biology of the Cell 11, 3539-3558.
[134] Yamada, S., Wirtz, D., and Coulombe, P.A. (2002). Pairwise assembly determines the intrinsic potential for self-organization and mechanical properties of keratin filaments. Molecular Biology of the Cell 13, 382-391.
[135] Yasui, Y., Amano, M., Nagata, K., Inagaki, N., Nakamura, H., Saya, H., Kaibuchi, K., and Inagaki, M. (1998). Roles of Rho-associated kinase in cytokinesis; Mutations in Rho-associated kinase phosphorylation sites impair cytokinetic segregation of glial filaments. Journal of Cell Biology 143, 1249-1258.
[136] Zatloukal, K., Stumptner, C., Fuchsbichler, A., Heid, H., Schnoelzer, M., Kenner, L., Kleinert, R., Prinz, M., Aguzzi, A., and Denk, H. (2002). p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. American Journal of Pathology 160, 255-263.
[137] Zhu, J.H., and Chu, C.T. (2010). Mitochondrial dysfunction in Parkinson's disease. J Alzheimers Dis 20, S325-S334.

連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top