脊髓小腦萎縮症第八型是一種漸進性的神經退化疾病，其致病的原因是由於染色體13q21上的ATXN8OS (又稱作SCA8,或KLHL1AS)基因在3’端外顯子的CTG三核苷酸不正常擴增所造成。目前對於此疾病的詳細致病機轉尚未了解，早期相關文獻指出ATXN8OS基因並不具有轉譯蛋白的功能，而可能是以anti-sense RNA影響對應股的KLHL1基因表現功能；然而最近文獻指出ATXN8OS的反譯股ATXN8，或許會轉譯出polyQ蛋白質，而polyQ蛋白質也正是許多型脊髓小腦萎縮症的致病原因；另外，也有研究指出在ATXN8OS基因上CTG三核苷酸擴增區域前，可能具有IRES活性，而使得此三核苷酸擴增轉譯出polyL毒性蛋白質。為了更進一步去了解ATXN8OS致病的分子機制，我們因而建立了ATXN8OS的轉殖小鼠模式。利用原核胚顯微注射的方法，將人類ATXN8OS基因帶有正常範圍(22)及致病範圍(150)兩種CTG擴增的基因片段，並連接了綠螢光報導基因，藉由NSE啟動子表現在小鼠的神經系統，以進一步了解CTG擴增對於小鼠造成的影響。從實驗結果中，我們發現帶有致病CTG擴增的轉殖小鼠，在小腦中有神經受損及缺失的情況發生，此外藉由行為測試也觀察到小鼠的異常行為，我們同時也將相同的基因架構轉殖進大鼠嗜鉻細胞瘤細胞株(PC12)，建立離體的模式，藉此平臺可快速觀測ATXN8OS過度表現會對於神經細胞所產生的影響；從實驗中我們也發現到帶有致病範圍CTG擴增的細胞，在低血清及神經生長因子的分化刺激下，比正常的細胞更容易死亡，且其神經分化的能力也較差，由這些研究結果，我們發現不管ATXN8OS過度表現在離體及活體內均造成神經傷害，這些結果將有利於在相關疾病的基因及藥物治療研究之應用。

Spinocerebellar ataxia type 8 (SCA8) was reported caused by an unstable CTG repeat expansion in the 3’ terminal exon of ATXN8OS (also named SCA, or KLHL1AS) gene on chromosome 13q21. How the trinucleotide expansion causes the disease is not clear now. Some studies indicate that ATXN8OS might not encode protein and play an anti-sense regulatory role on the sense strand gene, KLHL1. However, a recent study indicates that the opposite strand of ATXN8OS, ATXN8, encodes a polyglutamine expansion protein, which might explain the gain-of-function mutation of SCA8 disease as other polyglutamine-mediated SCAs. To further investigate the molecular mechanism of SCA8, a transgenic mouse model was established. The human ATXN8OS full-length cDNA with 22 or 150 CTG repeats in-frame fused with flag-EGFP was used as the transgene and driven by a neuron-specific-enolase (NSE) promoter. Our results show that the transgenic mice with expanded CTGs have some neuropathologies in the cerebella, including the neuronal cell loss and behavior abnormality. To have a quick platform to access the ATXN8OS overexpression effect on neuronal cell level, we also transfected constructs of ATXN8OS with 22 or 150 CTG repeats into the rat pheochromocytoma (PC12) cell line. We found that cells with expanded 150 CTG repeats were more vulnerable and showed reduced neuronal differentiation under low serum and NGF condition compared to cells with normal CTG expansion. With these models, we could gain some information about the molecular effects resulted from overexpression of ATXN8OS in vivo and in vitro, which should further provide more implications for the therapeutic design of SCA8 in the future.

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林玄原。(2007)。脊髓小腦運動失調症之族群遺傳分析與CTG三核苷重複擴增的分子致病研究。台灣師範大學研究所博士論文。
陳韋倫。(2006)。脊髓小腦萎縮症第八型致病基因分析及建立脊髓小腦萎縮症第八型離體及活體模式。台灣師範大學研究所碩士論文。
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