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研究生:李金玨
研究生(外文):Ghin-Chueh Lee
論文名稱:脊髓小腦共濟失調症:第八型脊髓小腦共濟失調症之外遺傳與細胞模式研究
論文名稱(外文):Spinocerebellar ataxia:Epigenetic and cell model studies of SCA type 8
指導教授:李桂楨李桂楨引用關係
指導教授(外文):Guey-Jen Lee-Chen
學位類別:碩士
校院名稱:國立臺灣師範大學
系所名稱:生命科學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:62
中文關鍵詞:脊髓小腦共濟失調症:第八型脊髓小腦共濟失調症之外遺傳與細胞模式研究
外文關鍵詞:Spinocerebellar ataxia:Epigenetic and cell model studies of SCA type 8
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摘要
第八型脊髓小腦共濟失調症(SCA8)是第一個被報導的單一三核苷重複擴增突變、由DNA兩股分別產生致病性的RNA (ATXN8OS)及蛋白質(ATXN8)產物的疾病。SCA8外顯性不完全,基因突變也見於極少數正常人及其他神經性疾病。ATXN8OS基因5’端有明顯的CpG島。本研究首先檢視正常人族群及帕金森氏症患者、原發性顫抖症及其他神經相關疾病患者族群之SCA8基因CTG重複變異,結果共發現一位正常人及兩位相關的肌肉營養不良症患者具CTG重複擴增的對偶基因。其次,在SCA8外遺傳研究方面,利用SCA8 CTG擴增的病人及其家屬及帶有SCA8 0~157個複合重複序列的胚胎腎細胞株DNA樣品,以PCR-based限制酵素及bisulfite定序技術,檢測ATXN8OS與KLHL1基因重疊序列上的CpG島甲基化情形。結果並未觀察到甲基化現象。另外也利用辨識緊密或疏鬆染色質結構的抗體及染色質免疫沈澱-PCR技術,來檢測SCA8基因的染色質結構。結果觀察到與CTG重複擴增相關的緊密染色質結構,但與DNA甲基化無關。最後,利用年齡、性別配對的正常人和CTG重複擴增病患的淋巴細胞株,探討對細胞自戕刺激物staurosporine或proteasome抑制劑MG-132的敏感性。病人淋巴細胞株在staurosporine (50 nM)及MG-132 (200 nM)濃度處理下,細胞死亡率顯著增加的結果,顯示SCA8的CTG重複擴增具細胞毒性。
Abstract
Spinocerebellar ataxia type 8 (SCA8) involves the expression of an expanded CTG/CAG combined repeats from opposite strands producing CUG expansion transcripts (ATXN8OS) and a polyglutamine expansion protein (ATXN8). SCA8 disease does not show complete penetrance and repeat expansions have been found among unaffected individuals and patients with other neurological diseases. An apparent CpG island was observed within the 5’ region of the ATXN8OS gene. In this study, we screened the SCA8 CTG repeats distribution in normal controls and in patients with various neurodegenerative diseases. A tatal of three subjects with expanded alleles was found, including one normal and two related oculopharyngeal muscular dystrophy. In the epigenetic studies, aberrant methylation in the overlapped ATXN8OS/KLHL1 gene exon 1 region was evaluated using DNA samples from patients with SCA8 expansions and stable HEK-293 lines carrying 0~157 combined repeats. PCR-based restriction enzyme assay and bisulfite-sequencing assay were performed for the measurement of CpG hypermethylation. No methylation was observed. Additionally, chromatin immunoprecipitation and PCR using antibody associated with repressed or open chromatin were performed to examine the chromatin structure of the SCA8 gene. A repeat length-dependent repression of chromatin structure, which is independent of DNA methylation, was observed. Finally, age and gender-matched lymphoblastoid cells with or without expanded SCA8 alleles were tested for their sensitivity to staurosporine (apoptotic stimulus) and MG-132 (proteosome inhibitor). The results of significant increase of cell death by staurosporine (50 nM) and MG-132 (200 nM) treatment further demonstrate that the expanded SCA8 repeats are toxic to human cells.
目錄 I
中文摘要 IV
英文摘要 V
圖表次 VI
壹、緒論 1
一、脊髓小腦共濟失調症(SCA) 1
二、第八型脊髓小腦共濟失調症(SCA8) 3
三、SCA8的可能致病機轉 4
(一) KLHL1的功能缺失(loss of function) 5
(二) RNA gain-of function 5
(三) PolyQ擴增蛋白 6
四、外遺傳(Epigenetic)修飾與基因表現的調節 7
(一) DNA甲基化 7
(二) 組蛋白修飾 8
(三) 三核苷酸重複擴增和染色質結構 8
五、SCA的淋巴細胞株模式研究 9
六、研究動機與目的 10
貳、研究材料與方法 12
一、研究材料 12
二、細胞株的培養及冷凍保存 12
三、基因組DNA萃取 13
四、SCA8 (CTG)n重複分析 14
五、PCR-based限制酶檢測 14
六、Sodium-bisulfat定序 15
七、染色質免疫沈澱-PCR (ChIP- PCR) 16
八、淋巴細胞的存活率分析 18
九、caspase-3活性分析 19
參、結果 20
一、SCA8 CTA/CTG重複之遺傳分析 20
二、SCA8外遺傳研究(epigenetic studies) 20
(一) H327、H600家族的DNA甲基化分析 20
(二) SCA8胚胎腎臟細胞株的DNA甲基化分析 22
(三) SCA8胚胎腎臟細胞株的染色質結構分析 23
(四) SCA8淋巴細胞株的染色質結構分析 23
三、 SCA8淋巴細胞株的細胞存活率分析 24
四、 SCA8淋巴細胞株的caspase-3活性分析 25
肆、討論 26
一、 SCA8 CTA/CTG重複之遺傳分析 26
二、 SCA8外遺傳研究 27
(一) DNA甲基化分析 27
(二) 染色質結構分析 28
(三) DNA甲基化與組蛋白修飾之關係 30
三、 SCA8淋巴細胞株的細胞存活率與caspase-3活性分析 31
伍、參考文獻 34
陸、附錄圖表 46
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