脊髓小腦運動失調症 (Spinocerebellar ataxias)為一群顯性遺傳的神經退化性疾病，患者小腦及腦幹區域發生漸進式的神經退化，其中第八型脊髓小腦運動失調症 (SCA8)與染色體13q21位置的ATXN8OS基因3’端非轉譯區CTG三核苷重複擴增相關；除此之外，目前根據前人研究顯示SCA8疾病除了與ATXN8OS CTG方向的擴增有關，其反向ATXN8基因之CAG擴增也可能扮演重要的角色。目前SCA8的致病機轉尚未十分明確，本論文主要核心為研究SCA8疾病之遺傳與分子機轉。首先，我們利用人類胚胎腎細胞 (Human embryonic kidney 293 cell lines)建立可被誘導並穩定表現包含不同長度CTG擴增的ATXN8OS細胞株並進行ATXN8OS RNA表現之研究，實驗結果顯示帶有較長重複擴增之細胞，其ATXN8OS RNA被誘導表現的倍數較高，可能是由於其RNA比較穩定所導致。利用螢光原位雜交技術，我們也觀察到在帶有較長重複擴增之細胞中有RNA foci的形成。本論文的第二部份為檢測ATXN8OS、ATXN8及KLHL1 RNA在正常個體及ATXN8OS CTG擴增病人淋巴細胞株 (lymphoblastoid cell lines)中之表現，實驗結果發現在病人之淋巴細胞中ATXN8 RNA表現量比正常人高並達顯著差異，推測可能與存在ATXN8啟動子中的-62 G/A多型性點有關。另一方面，雖然之前的研究認為ATXN8OS基因不會進行轉譯，但我們實驗室的研究證實了ATXN8OS基因中的開放解讀架構 (open reading frame, ORF)可以透過特殊IRES (internal ribosome entry segment)的轉譯活性製造出蛋白質，因此，ATXN8OS ORF蛋白質轉譯的調控機制以及ORF蛋白質在病理機制當中可能扮演的角色亦是本論文著重的議題。本論文中我們利用ATXN8OS融合EGFP基因證實了ATXN8OS RNA具有轉譯的能力，除此之外我們利用ATXN8OS ORF蛋白質的抗體研究ORF蛋白質在不同細胞株中的表現，並更進一步利用質譜技術分析ORF蛋白質之胺基酸序列。我們也發現在病人的淋巴細胞株中，ATXN8OS ORF蛋白質的表現量高於正常人。預期本論文的實驗結果，將有助於了解SCA8的致病機轉，找尋適當的治療目標，並可以將結果應用到其他相關的神經退化性疾病中。

The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases caused by a progressive degeneration of the cerebellum and brainstem. Among the SCAs, spinocerebellar ataxia type 8 (SCA8) involves the expression of a CTG/CAG expansion mutation from opposite strands producing CUG expansion transcripts (ATXN8OS) and a polyglutamine expansion protein (ATXN8). The pathogenic mechanism of ATXN8OS expansion is still unknown. The main purpose of this present proposal is to dissect the possible factors involved in SCA8 pathogenesis. Firstly, the stably induced cell lines expressing 0, 23, 88 and 157 CR exhibit low levels of ATXN8OS expression without doxycycline induction, and a repeat length-dependent repression of ATXN8OS expression was notable. Addition of doxycycline leads to 25~50 times more ATXN8OS RNA expression with a repeat length-dependent increase in fold of ATXN8OS RNA induction. The repeat length-dependent increase in induction fold is probably due to the increased RNA stability. RNA FISH experiments further revealed ribonuclear foci formation in cells carrying expanded 88 and 157 CR. Our results demonstrate that the expanded CUG-repeat tracts may affect ATXN8OS RNA expression and stability through epigenetic and post-transcriptional mechanisms. Secondly, ATXN8 expression level is significantly higher in lymphoblastoid cells with SCA8 large alleles than that of the control cells. Our results suggest that ATXN8 gene -62 G/A polymorphism may be functional in modulating ATXN8 expression. Lastly, although reported non-coding, existence of IRES (internal ribosome entry segment) activity in the 5’ UTR sequence of ATXN8OS has been demonstrated in our previous studies. Expression of chimeric constructs with an EGFP gene fused in-frame to ATXN8OS ORF demonstrated ATXN8OS is translatable and the ORF protein formed aggregates and co-localized with mitochondria. Moreover, the ORF expression was validated in different human cells using ORF antiserum. ATXN8OS ORF was further confirmed by LC-MS/MS. The expression of ORF protein was significantly higher in lymphoblastoid cells carrying expanded ATXN8OS. The results of this study may suggest a broader hypothesis for further research in explaining the expanded CTG leading to neuronal dysfunction in SCA8.

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