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研究生:陳美璇
研究生(外文):Chen, Mei-Hsuan
論文名稱:Caspase水解GFAP產生無法聚合的蛋白片斷促進中間絲的不正常聚集
論文名稱(外文):Caspase Cleavage of GFAP Produces an Assembly-Compromised Proteolytic Fragment that Promotes Filament Aggregation
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:高茂傑林玉俊劉銀樟吳宗遠
口試委員(外文):Kao, Mou-ChiehLin, Yu-chunLiu, Yin-ChangWu, Tzong-Yuan
口試日期:2017-12-29
學位類別:博士
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:2017
畢業學年度:106
語文別:英文
論文頁數:39
中文關鍵詞:亞力山氏症中間絲蛋白
外文關鍵詞:Alexander diseaseC-terminal GFAPCentral nervous systemGlial fibrillary acidic proteinIntermediate filamentN-terminal GFAP
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Caspase (cysteine-containing asparte-specific protease ) 蛋白質脢水解GFAP神經膠質纖維酸性蛋白質(glial-specific intermediate filament protein, GFAP) 一連串的蛋白質脢解作用(proteolysi cascade),此死亡訊息送至死亡路徑去破壞DNA而使細胞死亡,此時細胞的蛋白質結構被破壞會引起中間型蛋白絲的不正常聚集。發生的逆境反應所媒介的下游訊號傳遞可能是造成亞歷山大氏症的一個關鍵因素。前人研究顯示中樞神經系統內的星狀細胞的中間型蛋白絲GFAP基因突變會引起亞歷山大氏症,而基因突變所引起的不正常中間絲蛋白失去支持細胞結構的能力是引起亞歷山大氏症的可能原因之一。這裡我們發現caspase蛋白質脢解的作用會讓GFAP序列分成carboxyl-terminal fragment (C-GFAP)端蛋白無法完成結構, 而 amino-terminal fragment (N-GFAP) 端之蛋白絲會不正常聚集,進而影響正常細胞完成正確結構。將利用誘導表現的細胞培養模式來建立中間型蛋白絲GFAP基因突變所造成的蛋白質聚合,逆境反應的誘發,為了再次確認caspase媒介的下游訊號傳遞蛋白質結構破壞時會引起中間型蛋白絲的不正常聚集及功能失調的關連性。此實驗進而研發出抗原決定位的抗體能夠辨認caspaes引起死亡路徑去破壞DNA而使細胞死亡時引發蛋白質結構改變的片段。這些在細胞層次上的關連性將有助於了解疾病形成的過程。此研究成果將可能應用於臨床上的治療,這些方法不但可以應用在亞歷山大氏症,對於治療病源於其他膠質細胞具有類似細胞骨架功能失調所造成的神經性疾病,也會有相當大的助益。
Glial fibrillary acidic protein (GFAP) is the major constituent of the glial intermediate filaments that are expressed mainly in mature astrocytes of the central nervous system. Dominant mutations in the gene encoding GFAP cause Alexander disease, a primary genetic disorder of astrocytes that typically affects young children. The expression of mutant GFAP or overexpression of wild-type GFAP promotes the formation of cytoplasmic aggregates, with caspase activation and GFAP proteolysis. In this study, we report that GFAP is cleaved specifically by caspase 6 at VELD225 in its L12 linker domain in vitro. Caspase cleavage of GFAP at Asp225 produces two major cleavage products. While the carboxyl terminal fragment (C-GFAP) is unable to assemble into filaments, the amino-terminal fragment (N-GFAP) forms filamentous structures that are variable in width and prone to aggregation. The effect of N-GFAP is dominant, thus affecting normal filament assembly in a way that promotes filament aggregation. Transient transfection of N-GFAP induces the formation of GFAP-containing aggregates, which also disrupt the endogenous networks of intact GFAP in a human astrocytoma cell line. In addition, we generated a caspase cleavage site-specific antibody that recognizes caspase-cleaved but not intact GFAP, as determine by immunoblotting and immunofluorescence. Using this antibody, we demonstrate the presence of the caspase-generated GFAP fragment in transfected cells expressing a disease-causing mutant GFAP and in two types of AxD models that have previously been shown to have varying levels of GFAP accumulation in different regions of the central nervous system. These results imply that caspase-mediated cleavage of GFAP correlates with elevated GFAP in the context of GFAP mutation and accumulation. Moreover, we provide evidence to suggest that caspase cleavage of GFAP has important functional consequences, decreasing GFAP filament solubility by changing filament–filament interactions in a way that promotes aggregation.
Abstract(I)
Abbreviation(III) Contents(I)
VChapter 1 Introduction(1)
Chapter 2 Materials & Method s( 3)
2.1 Plasmid construction and site-directed mutagenesis(3)
2.2 Expression and purification of recombinant GFAPs(3)
2.3 Caspase cleavage of GFAP in vitro(4)
2.4 In vitro assembly and sedimentation assay(4)
2.5 Electron microscopy(5)
2.6 Cell cultures and transient transfection(5)
2.7 Generation of caspase cleavage site-directed antibody(5)
2.8 Cell fractionation, immunoblotting and immunoprecipitation(6)
2.9 Cell fractionation, immunoblotting and immunoprecipitation(6)
2.10 Immunological analyses of GFAP proteolysis in transgenic mice(7)
Chapter 3 Results (9)
3.1 Specific cleavage of GFAP at Asp225 by caspase 6 in vitro (9)
3.2 Assembly properties of the caspase-generated cleavage products (9)
3.3 In vitro analysis of preassembled materials from intact GFAP and caspase cleavage products(11)
3.4 Generation and characterization of site-directed caspase cleavage antibody(12)
3.5 Effects of N-GFAP on the endogenous GFAP networks in U343MG cells(13)
3.6 Detection of N-GFAP in transgenic mice overexpressing human GFAP(14)
Chapter4 Discussion(16)
4.1 Caspases play an essential role during apoptotic cell death(16)
4.2 Structural consequences of caspase-mediated GFAP proteolysis(17)
4.3 Functional consequences of caspase-mediated GFAP proteolysis(18)
Reference (22)
Figure legends(30)
Figure 1(30)
Figure 2.(31)
Figure 3.(32)
Figure 4.(33)
Figure 5.(34)
Figure 6. (36)
Figure 7.(38)
Figure 8.(39)
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