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研究生： 黃于珊
Huang, Yu-Shan
論文名稱： 以生化及細胞分析來探討亞歷山大疾病之GFAP突變蛋白對星狀細胞的影響
Biochemical and cellular analyses to study the effects of Alexander disease-associated GFAP mutations in astrocytes
指導教授： 彭明德
Perng, Ming-Der
口試委員: 焦傳金
Chiao, Chuan-Chin
高茂傑
Kao, Mou-Chieh
劉銀樟
Liu, Yin-Chang
黃兆祺
Hwang, Eric
學位類別： 博士
Doctor
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： 2019
畢業學年度： 107
語文別： 英文
論文頁數： 105
中文關鍵詞： 膠質纖維酸性蛋白 、星狀膠質細胞 、歷山大疾病 、突變
外文關鍵詞： Glial Fibrillary Acidic Protein, Astrocyte, Alexander disease, Mutations
相關次數： 點閱：2  下載：0 
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    • 膠質纖維酸性蛋白（GFAP）是第III型的中間絲蛋白，主要是存在在中樞神經系統的星狀膠質細胞中。GFAP的功能是細胞骨架，從細胞核延伸到細胞膜，使細胞成形。過去已經報導突變的GFAP與某些疾病有很多關係;最著名的是亞歷山大疾病（AxD），一種罕見的神經退行性疾病，多發於兒童。AxD的特徵是星形膠質細胞內存在大量的膠質聚集，稱Rosenthal fibers，由GFAP、αB-crystallin 和HSP27、及其他未鑑定的蛋白質所組成。有許多報導指出62種不同的GFAP突變，其中一些是missense或frame-shift mutations。然而，GFAP突變的Transient expression和動物模型對於表現出phenotype（在AxD中的Rosenthal fibers）有一些挑戰和困難。為此，我們在小鼠DBT細胞建立了tet -on系統來表現GFAP，接著又建立了pLEX -MCS病毒來感染大鼠星狀細胞進而表現GFAP。 在tet -on系統中，我們發現GFAP突變R416W的細胞質聚集增加了細胞活力，並通過Autophagy和UPS來分解蛋白。在 PLEX -MCS病毒感染系統，我們發現，某些不同類型的突變GFAP（Δ4，κGFAP，IDF，ΔT 和E312 *）的聚集會導致的大鼠星形細胞細胞中的線粒體也聚集。我們另外發展出特定的小鼠GFAP專一性抗體以檢測來自轉基因動物，人類患者或是AxD動物模型中的GFAP。

    Glial Fibrillary Acidic Protein (GFAP) is type III intermediate filament and major astrocytic protein in central nerve system. The functions of GFAP are cytoskeleton that extend from nucleus to cell membrane to give cells their shape. Mutant GFAPs have been described to have lots of relation with some disorders; most famous is the Alexander disease (AxD), a rare neurodegenerative disease mostly in children. AxD is the presence of inclusion bodies within astrocytes known as Rosenthal fibers, consisting of ubiquitinated GFAP, the small stress proteins αB-crystallin and HSP27, and likely other unidentified proteins. There are many reports point out 62 different GFAP mutation, some of them are missense or frame-shift mutations. However, transient expression system and animal model for GFAP mutation have some challenge to show the phenotype of inclusion (Rosenthal fiber). For this reason, we have stablished the doxycycline inducible tet-on system in mouse DBT stable cell lines and pLEX-MCS lentivirus infection system in rat primary astrocyte cells. In tet-on system, we found the cytoplasmic aggregation of GFAP mutant R416W (the amino acid residue 416 Arginine was changed to Tryptophan) increased the cell viability and degraded by autophagy and UPS synchronously. In pLEX-MCS lentivirus infection system, we demonstrated that different types of mutants GFAP (∆4, κGFAP, IDF, ∆T and E312*) aggregations would cause mitochondrial co-localization in rat primary astrocyte cells. Moreover, we characterized the GFAP antibody epitope mapping and generated the mouse GFAP-specific antibody to detect GFAP from the samples of the transgenic animal, human patients, and cell-based models of AxD.

    Table of contents Abstract………………………………………….………………………Ⅰ 摘要……………………………………………………………………Ⅱ Acknowledgement……………………………….……….……………..Ⅲ Table of contents…………………………………..…………………….Ⅳ Chapter 1: Introduction…………………………….……………………..1 1.1 Astrocyte………………………………………..…………………….1 1.2 Glial fibrillary acidic protein (GFAP)……………….………………..2 1.3 Neurological disorder Alexander disease (AxD)…….………………..3 1.4 GFAP mutations…………………………………….………...………4 1.5 GFAP mutants cell models………………………….…………...……5 1.6 GFAP mutants animal model……………………….……………..….6 1.6.1 Overexpression of wild type human GFAP in transgenic mice….......6 1.6.2 Expression of GFAP mutants knockin mice and Drosophila model...7 1.7 GFAP-specific antibodies…………………………………………….9 1.8 Specific aims of this study…………………………………………….9 Chapter 2: MATERIALS AND METHODS………………………….…10 2.1 Plasmids construction………………………………………….……10 2.2 Site-directed mutagenesis……………………………………..……..11 2.3 Cell cultures…………………………………………………...…….11 2.4 Establishment of Tet-on inducible DBT stable cell lines that express GFAP…………………………………………………..………………..12 2.5 Rat/mouse primary astrocyte cells…………………………….……..12 2.6 Rat primary neurons…………………………………...…………….13 2.7 Lentiviral production and transduction………………………….…...13 2.9 Immunofluorescence (IF) microscopy……………………..………..14 2.10 SDS-PAGE and Western blotting (WB)………………….…..…….15 2.11 Flow cytometry…………………………………………...………..16 2.12 Colloidal coomassie blue G-250 protein stain…………….………..16 2.13 Protein identification by mass spectrometry……………..…………17 2.14 MTT assay…………………………………………….……………18 2.15 Subcellular fractionation…………………………………..……….18 2.16 Live cell staining with MitoTraker® Red……………..……………19 2.17 Statistics………………………………………………...………….19 Chapter 3: RESULTS……………………………………….…….……..20 3.1 Establishment of stable clones of doxycycline inducible Tet-on human wild type and mutant R416W GFAP in mouse DBT cell lines……...……20 3.2 Cell aggregation patterns in tet-on R416W GFAP in DBT stable clones…………………………………………………………...……….21 3.3 Cell viability was increased tet-on R416W GFAP in DBT stable clones………………………………………………………...………….21 3.4 GFAP proteolytic fragment was increased in tet-on R416W GFAP DBT stable clone after induction…………………………..…………….……22 3.5 Mass spectrometric identification of GFAP in inducible DBT stable cells………………………………………………………….…………..23 3.6 Involvement of ubiquitin-proteasome system (UPS) and autophagy in inducible DBT stable cells…………………………………..…………..23 3.7 To investigate the distribution of GFAP in relation to mitochondria by transient expression and co-stained mitotracker in primary astrocytes..…26 3.8 Aggregation formations of mutant GFAPs by lentivirus infection in rat primary cells……………………………………………...………….….27 3.9 To investigate the distribution of GFAP in relation to mitochondria by lentivirus infection and co-infected MitoDsRed in primary astrocytes.....29 3.10 Involvement of autophagy and apoptosis in GFAPs…………….….30 3.11 Construction of GFAP variants for GFAP antibody epitope mapping……………………………………………………...………….31 3.12 GFAP and the mouse-specific sequence used for antibody generation……………………………………………………...………..32 3.13 Validation of mGFAP antibody by immunoblotting using samples from cell lysates, transgenic mice overexpressing hGFAP and R236H GFAP knock-in mice…………………………………………..….……..32 3.14 Validation of mGFAP antibody in immunofluorescence using samples from DBT ten-on cell lines and primary rat and mouse astrocyte cells………………………………………………………….…………..34 Chapter 4: Discussion………………………………………...…………35 4.1 R416W GFAP mutant…………………………………….…...……..35 4.2 Tet-on system to GFAP mutant……………………………..………..37 4.3 Mass spectrometric analysis………………………………...……….39 4.4 Lentiviral transduction of GFAP into primary astrocytes…….……...41 4.5 Mutant GFAP cause disease by promoting GFAP aggregation…....…43 4.6 Strategies for reducing GFAP expression………………………....…46 4.7 Mitochondria and GFAP mutants………………………………....…48 4.8 GFAP epitope mapping…………………………………………..….51 References……………………………………………………...……….54 Figures…………………………………………………………….…….69 Tables………………………………………………………………..…..88 Appendix……………………………………………………………..…92

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