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研究生：	李麗卿 Li-Ching Lee
論文名稱：	第十七型脊髓小腦共濟失調症致病機轉：伴隨蛋白的保護功能與TATA結合蛋白CAG三核苷重複擴增造成不正常蛋白質摺疊之研究 Spinocerebellar ataxia 17 (SCA17) pathogenic mechanisms: Chaperones function and misfolding proteins caused by the expanded polyglutamine in TATA-binding protein
指導教授：	李桂楨 Lee, Guey-Jen
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2009
畢業學年度：	97
語文別：	英文
論文頁數：	97
中文關鍵詞：	第十七型脊髓小腦萎縮症、TBP多麩醯胺擴增、細胞模式、差異性螢光標記二維電泳、伴隨蛋白A5 、伴隨蛋白A8 、伴隨蛋白B1 、基因表現分析
英文關鍵詞：	spinocerebellar ataxia type 17, TBP expansion, cell model, 2D-DIGE, HSPA5, HSPA8, HSPB1, gene expression analysis
論文種類：	學術論文
相關次數：	點閱：409 下載：3
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摘要
遺傳性第十七型脊髓小腦萎縮症(SCA17)與染色體6q27位置的TATA binding protein (TBP)基因的CAG三核苷重複擴增相關。TBP廣泛表現在中樞神經系統及周邊組織。臨床上SCA17病患症狀很廣泛，致病機轉亦未完全清楚。為探討SCA17疾病致病機轉，我們建立短暫大量表現及穩定誘導正常TBP-Q36及多麩醯胺擴增TBP-Q61的人類胚胎腎293細胞，並利用差異性螢光標記二維電泳、質譜、免疫轉漬等方法，分析蛋白質的表現。以doxycycline誘導表現後，擴增的TBP-Q61形成聚集，且活化的caspase-3皆顯著增加。蛋白質體分析顯示23個蛋白質的差異表現在1.35倍以上。進一步以二維電泳及西方免疫轉漬確認HSPA5、HSPA8、PARK7的差異表現。淋巴細胞的蛋白質分析顯示，與正常人的淋巴細胞相較，帶有多麩醯胺擴增TBP的病患淋巴細胞，其HSPA5、HSPA8、HSPB1的表現顯著下降。進一步利用lenti病毒轉染，檢視geldanamycin對HSPA5表現及SCA17性狀的調節。在多麩醯胺擴增TBP等位基因的檢測方面，分析了臺灣地區帕金森氏症、阿茲海默氏症、非典型帕金森氏症候群患者的TBP基因CAG 三核苷酸重複，共發現6個擴增的等位基因(44 ~ 46Q)。此類非典型小腦萎縮症病患的報導，有助於疾病性質的瞭解。綜合上述，實驗結果顯示利用蛋白質體分析來找出和SCA17疾病致病機轉相關的差異表現蛋白，有助於致病機轉的瞭解，並可能依據來發展治療策略。

Abstract
Expansion of the CAG repeat of the TATA-box binding protein (TBP) gene has been identified as the causative mutations in spinocerebellar ataxia 17 (SCA17). TBP is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The underlying molecular changes of SCA17 are rarely explored. To study the molecular mechanisms underlying SCA17, transient overexpressed and stably induced isogenic 293 cells expressing normal TBP-Q36 and expanded TBP-Q61 were generated and analyzed the expressed proteins using two-dimensional difference in gel electrophoresis (2D-DIGE), followed by mass spectrometry and immunoblotting. Upon induction with doxycycline, the expanded TBP-Q61 formed aggregates with significant increase in cleaved caspase-3. Proteomics study identified a total of 23 proteins with expression changes greater than 1.35 fold. The altered expression of HSPA5, HSPA8 and PARK7 were further validated by 2D and Western immunoblot analyses. In lymphoblastoid cells, significant lower HSPA5, HSPA8 and HSPB1 expression levels were observed in cells with expanded TBP than that of the control cells. Using lentiviral transduced human neuroblastoma cell models, the effects of geldanamycin on HSPA5 expression and SCA17 phenotype were assessed. Genetic screening of triplet expansion in the TBP gene in Taiwanese Parkinson's disease, Alzheimer's disease and atypical parkinsonism revealed a total of 6 expanded alleles (44 ~ 46) in patients group. Reports of additional patients are crucial for better understanding the nature of the disease. Together, this study illustrates the utility of proteomics to identify alterations of proteins which may shed insights into the pathogenesis and lead to therapeutic interventions for this disease.

Index      I
Abstract (Chinese)    V
Abstract      VI
List of figures and tables    VII
Introduction    1
Spinocerebellar ataxia 17: autosomal dominant cerebellar ataxia caused by the expanded polyglutamine in TATA-binding protein    1
Polyglutamine expansion diseases: plausible pathogenic mechanisms    2
Protein misfolding and aggregation    2
Oxidative stress and neuroprotection    3
Protein misfolding and endoplasmic reticulum stress    4
Transcriptional dysfunction    5
Potential therapeutic invention: chaperone activation, transcription activation and combinatorial drug therapy    6
Chaperone activation to reduce protein aggregation    6
Transcription activation to reduce protein aggregation    7
Candidate drugs and combinatorial drug therapy    7
Cellular model approach for polyQ diseases: transient/induced and neuronal/non-neuronal    8
Transient murine Neuro-2a model    8
Inducible stable human 293 cell model    8
Human neuroblastoma cell model    9
Lymphoblastoid cell lines: resource of biomaterials in research of neurological disorders    10
Proteomic approach for studying polyQ expansion diseases: 2-dimensional fluorescence difference in gel electrophoresis    11
Aims     13
Materials and methods     15
I. To generate stably induced isogenic 293 cells expressing normal and expanded TBP and analyze the expressed proteins using 2D-DIGE     15
TBP cDNA constructs    15
Cell cultivation    16
Transfection    16
Dot-blot filter retardation assay    17
Isogenic 293 cell lines    17
Immunocytochemical staining    18
Real-time qPCR    18
Western blotting    19
Caspase-3 activity    19
Protein samples preparation for proteomic analysis    19
Minimal labeling with CyDye Fluors for DIGE    20
IPG strip rehydration and first-dimension isoelectric focusing (IEF)    21
Second-dimension SDS-PAGE    21
Image analysis    22
Gel staining with SYPRO Ruby    22
In-gel digestion    22
Mass spectrometry, protein identification and confirmation    23
Metacore network analysis    24
II. To validate the identified altered expressed proteins using lymphoblastoid cell lines generated from patients with expanded TBP    24
Lymphoblastoid cell lines    24
Western blot analysis    25
III. To generate neuroblastoma SK-N-SH cell models expressing normal and expanded TBP    25
Cell cultivation and transfection    26
Lentiviral expression constructs    26
Lentivirus package and cell transductions    26
SK-N-SH stably transduced cell lines    27
IV. To assess the effects of geldanamycin and HDAC inhibitors on SCA17 phenotype    27
Cell cultivation    27
MTT assay    28
Drug effects on aggregate formation    28
Neuroblastoma cells differentiation and neurite outgrowth analysis    28
V. To set up SCA17 database in various Taiwanese disease populations    29
Subjects    29
Genetic analysis of SCA17 repeats    30
Results…    32
I. Generation of stably induced isogenic 293 cells expressing normal and expanded TBP and analysis of the expressed proteins    32
Cloning and expression of TBP constructs    32
Isogenic TBP cell lines    33
2D-DIGE analysis of the isogenic TBP cell lines    34
2D and Western immunoblot confirmation of altered HSPA5, HSPA8 and PARK7 expression    35
Overexpression of HSPA5 to reduce the aggregate formation caused by expanded TBP    35
Metacore network analysis    36
II. Validation of the altered expressed HSPA5, HSPA8 and HSPB1 using lymphoblastoid cell lines generated from patients with expanded TBP    36
Lymphoblastoid cell lines establishment    36
Analysis of HSPA5, HSPA8, HSPB1 and PARK7 expression    37
III. Generation of neuroblastoma SK-N-SH cell models expressing normal and expanded TBP    38
Transient transfected SK-N-SH cell model    38
Stably transduced SK-N-SH cell model    38
IV. Assessment of geldanamycin and HDAC-inhibitors on SCA17 phenotype    39
Drug assessment using transient transfected HEK-293 cells    40
Drug assessment using transient transduced SH-SY5Y cells    40
V. SCA17 database in various Taiwanese disease populations    41
Frequency distributions of SCA17 repeat lengths    41
Sequence analysis of SCA17 expanded alleles    41
Discussion    43
I. Stably induced isogenic 293 cell model    43
II. Lymphoblastoid cell model    46
III. Neuroblastoma cell model    47
IV. Assessment of geldanamycin and HDAC inhibitors    48
V. Genetic analysis of SCA17 repeat lengths    49
VI. Future study on diseases pathogenesis    50
VII. Conclusion    51
References    53

List of figures and tables
Figure 1. Expression of TBP cDNA constructs    73
Figure 2. Expression of TBP cDNA constructs in transiently transfected HEK-293 cells    75
Figure 3. Diagram of the Flp-InTM T-RExTM system    76
Figure 4. Expression of TBP cDNA constructs in stably induced isogenic 293 cells    78
Figure 5. 2D image of soluble proteins from isogenic 293 cells    79
Figure 6. 2D and Western immunoblot analyses of the vector only and isogenic TBP lines using HSPA5, HSPA8, PARK7 and β-actin antibodies    80
Figure 7. Overexpression of HSPA5 in SCA17 transient cell model    81
Figure 8. The best ranked proteome networks delivered from the shortest path net work analysis with 1.35 threshold for 2D-DIGE data    82
Figure 9. Lymphoblastoid cell lines from normal controls and TBP expansion patients    83
Figure 10. Expression of TBP cDNA constructs in SK-N-SH cells    85
Figure 11. Titration of recombinant TBP-Q36 and TBP-Q61 lentiviral stocks    86
Figure 12. Expression of TBP cDNA constructs in lentiviral transduced stable SK-N-SH lines    87
Figure 13. The cytotoxicity of geldanamycin and HDAC inhibitors to 293FT cells    88
Figure 14. The effects of geldanamycin and HDAC inhibitor pre-treatment on aggregate formation in HEK-293 cells transiently expressed expanded TBP    89
Figure 15. Drug assessment using differentiated SH-SY5Y cells    90
Figure 16. Distributions of the SCA17 repeat lengths in controls and patients with PD, AD, or atypical parkinsonism    92
Table 1. Experimental design of 2D-DIGE gels and fluorophore labeling scheme    93
Table 2. Summary of the proteins identified by using 2D-DIGE and MALDI/TOF MS    94
                                

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