The Alexander disease causing mutations of GFAP are deleterious to filament assembly and network formation

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研究生：	林淑娟 LIM, SUH CIUAN
論文名稱：	The Alexander disease causing mutations of GFAP are deleterious to filament assembly and network formation 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 Perng, Ming-Der
口試委員:	張壯榮李文權
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
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：	GFAP, mutation, Alexander diasease, intermediate filament, small heat shock proteins, phosphorylation, stress
相關次數：	點閱：2 下載：0
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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

                                

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