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研究生:游雅君
研究生(外文):Ya-Chun Yu
論文名稱:脊髓小腦萎縮運動失調症的細胞模型研究
論文名稱(外文):Construction of Spinocerebellar Ataxia Type 17 Cellular Models Studies of Spinocerebellar Ataxias in Cellular Models
指導教授:謝明麗謝明麗引用關係
指導教授(外文):Mingli Hsieh
學位類別:碩士
校院名稱:東海大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:108
中文關鍵詞:氧化壓力多醯麩胺酸蛋白榖胱甘肽榖胱甘肽還原酶粒線體去氧核醣核酸脊髓小腦萎縮運動失調症第三型脊髓小腦運動失調症第十七型
外文關鍵詞:oxidative stresspolyglutamineglutathioneglutathione reductasemitochondrial DNAspinocerebellar ataxia type 3 diseasespinocerebellar ataxia type 17 diseaseSK-N-SH
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第一章
探討第三型脊髓小腦運動失調症在細胞模型的氧化還原能力

脊髓小腦運動失調症候群是一種體染色體顯性遺傳疾病,其中有六種亞型分別位於不同基因序列上的CAG三核苷酸(多麩酸胺)的重複序列所致,這六型分別為SCA1、2、3、6、7及17。這些類型的疾病中,CAG的重複序列會被轉錄轉譯成多麩酸胺。不正常的多麩酸胺會造成毒性的傷害,並且在細胞質與核內中產生堆積現象,導致細胞死亡。不過,多麩酸胺的突變是如何導致細胞死亡的詳細機制,至今仍不清楚。過去的研究指出,活氧分子或自由基會促進細胞的氧化壓力增加,是神經退化疾病重要的致病機制。一般相信,抗氧化系統中的非酵素及酵素分子,在哺乳類動物中樞神經系中扮演著移除氧化劑的角色,用以對抗神經退化疾病所產生的氧化壓力。我們過去的研究是利用SCA3疾病模型細胞株,在比較SK-N-SH及SK-N- SH-MJD78(具有全長78個麩酸胺重複序列的ataxin-3蛋白)細胞時發現,含有全長突變蛋白的SK-N-SH對於tBH具有較高的敏感性。因此,本實驗藉由GSH/GSSG比例的改變,證實這種擁有全長突變蛋白的細胞株,其氧化壓力確實高於親代正常細胞株。此外,SK-N- SH-MJD78與COS-7-MJD78-GFP細胞株在正常培養下,觸酶、榖胱甘肽還原酶與超氧物歧化酶的活性均有明顯下降,榖胱甘肽還原酶的蛋白質表達亦在突變細胞顯著下降。由於細胞遭受到氧化壓力時,粒線體DNA容易受到損害,因此從粒線體DNA複製數的結果發現,在攜帶有突變ataxin-3的早期代數SK-N-SH-MJD的確承受較大的氧化傷害。綜合上述結果,我們推論,突變ataxin-3蛋白可能會影響這些氧化還原酵素的活性,進而使突變細胞無法有效的移除O2-與H2O2,以及促使粒線體DNA出現突變或缺失,導致粒線體功能缺失。因此,我們認為氧化壓力所引發的細胞傷害,在SCA3疾病細胞進入程序性死亡的過程中,應扮演非常重要的角色。



第二章
脊髓小腦運動失調症第十七型的細胞模型建立

脊髓小腦運動失調症第十七型(Spinocerebellar ataxia type 17)屬於體染色體顯性神經性退化疾病的一種,發病原因來自於TATA- binding protein TBP)基因上的CAG/CAA擴增所致。TBP是真核細胞中一種重要的基本轉錄因子,過去研究發現正常TBP會與許多突變的多醯麩胺酸蛋白構成包涵物,進而堆積在細胞質或細胞核內。在TBP的N端序列上具有一段多醯麩胺酸序列,若這段多醯麩胺酸不正常擴增,則導致脊髓小腦運動失調第十七型的產生。過去的實驗並無針對第十七型建立穩定表達的細胞模型,故本實驗構築表達不同多麩酸胺序列的TBP質體,並用來建立SCA17的細胞模型。我們先將這些質體送入COS-7細胞中進行短暫性的基因表達,發現突變的TBP較正常TBP容易增加細胞凋亡的數目。此外,我們利用表達不同擴增CAG/CAA片段的TBP蛋白,建立穩定表達的細胞株,其中六株細胞經西方點墨法證實,分別含有36、45、54及109個多醯麩胺酸的重複序列。進一步分析發現此六株細胞在正常培養下,其生長曲線並無顯著差異。除此之外,此六株細胞的熱休克蛋白(Hsp90、70、60及27)表達量並無明顯差異。值得注意的是在這些穩定表達的細胞株中,發現COS-7-TBP-109Q-4的Bcl-2表達量較COS-7-TBP-36Q-4低。而這些穩定表達不同TBP的細胞株,未來將用來分析更多SCA17疾病在分子層次上的致病機制。同時我們也正構築穩定表達不同長度TBP的神經細胞株,希望未來能更了解不正常多醯麩胺酸擴增的TBP蛋白,在神經退化性疾病SCA17致病機制上所扮演的角色。
Chapter 1
Studies of Glutathione and Antioxidant Enzyme Activities in Cellular Models of Spinocerebellar Ataxia Type 3 Disease

Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited disorders. Six kinds of spinocerebellar ataxias are caused by CAG trinucleotide repeat expansion in the coding region of the respective genes, including SCA1, 2, 3, 6, 7 and 17. In all cases, the CAG repeats are transcribed and translated into polyglutamine tracts. The nature of the toxic insult of the mutant proteins will cause aggregation in the nucleus and cytoplasma and eventually lead to cell apoptosis. A poly(Q) mutation and its biological consequences in each disease are unclear. It is known that oxidative stress, induced by reactive oxygen species (ROS) or free radicals, plays an important role in pathogenesis of neurodegenerative disorders. Nonenzymatic and enzymatic components in the antioxidative system play critical role(s) to against oxidative stresses in the mammalian central neurous system. Our previous study showed that human neuroblastoma SK-N-SH cells stably transfected full-length SCA3 with 78 CAG repeats was more sensitive to t-butyl hydroperoxide (tBH). Evidenced by alterations in GSH/GSSG ratios, my results demonstrated that the mutant SCA3 cells showed greater oxidative stress than the parent cells. In addition, both SK-N-SH-MJD78 and COS-7-MJD78 -GFP cell lines have the lower levels of catalase, glutathione reductase and superoxide dismutase when compared to the wild-type cell lines under the normal growth condition. Furthermore, the expression of glutathione reductase decreased in COS-7-MJD78-GFP mutant cells compared to that of COS-7-MJD26-GFP normal cells. It is known that when cells are under oxidative stress, the mitochondrial DNA is prone to damage. Our results further demonstrated that mitochondrial DNA copy number of mutant cells is reduced when compared to that of the parent cells. Our results indicated that mutant ataxin-3 might influence the activity of enzymatic components to remove O2- and H2O2 efficiently, and promote mitochondrial DNA mutation or deletion, which leads to dysfunction of mitochondria. Therefore, we suggested that the cell damage caused by greater oxidative stress in SCA3 mutant cells plays an important role, at least in part, in the cell apoptotic pathway.



Chapter 2
Construction of Spinocerebellar Ataxia Type 17
Cellular Models

Spinocerebellar ataxia type 17 (SCA17), an autosomal dominantly inherited disease, is caused by an abnormal CAG/CAA expansion in the TATA-binding protein gene (TBP) in eukaryotic cells. TBP is an important general transcription factor. Previous studies found that normal TBP would accumulate with other mutant polyglutamine to form inclusion bodies, and then aggregate in cytoplasm or nucleus. The abnormal polyglutamine expansion in the N-terminal region of TBP causes SCA17. To our best knowledge, no SCA17 stable cell lines were previously established, therefore, I constructed TBP mammalian expression clones with a range of polyglutamine expansions to establish SCA17 cellular models. The results from transient transfection demonstrated that COS-7 transfected with mutant TBP showed increased apoptotic cells, when compared to cells containing the wild-type TBP. Furthermore, evidenced by western blotting, six COS-7 cell lines stably transfected with different TBP constructs containing various length of CAG/CAA repeat expansion, including 36, 45, 54 and 109 repeats, were established during my study. All the six stable cell lines showed similar growth curve under normal growth condition. The expression of heat shock proteins (Hsp90, 70, 60 and 27) of these six cell lines revealed no significant difference under normal growth condition. It is noted that expression of Bcl-2 decreased in COS-7-TBP109Q-4 when compared to that of COS-7-TBP36Q-4. Meanwhile, stably transfected neuroblastoma cells with different polyglutamine expansion of TBP are under way to study the molecular mechanism in neurodegenerative diseases. In the future, these stably transfected cell lines will be used for more detailed analysis of molecular pathogenesis of SCA17.
序論 2-3

第一章:探討第三型脊髓小腦運動失調症在細胞模型的氧化還原能力
中文摘要 5-6
英文摘要 7-8
前言 9-16
材料與方法 17-25
結果 26-37
討論 38-43
圖表 44-58

第二章:脊髓小腦運動失調症第十七型的細胞模型建立
中文摘要 60-61
英文摘要 62-63
前言 64-67
材料與方法 68-74
結果 75-80
討論 81-85
圖表 86-95
參考文獻 96-106
附錄 107-108
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