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.

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