脊髓小腦萎縮症第八型是一種晚發型自體顯性遺傳的神經退化疾病，其致病的原因是由於染色體13q21上的ATXN8OS基因在3’ 端外顯子上有一段不正常擴增的CTG三核甘酸所造成。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質的功能，然而，最近的文獻對於ATXN8OS基因，以及其對應股的ATXN8基因，支持一種雙向轉錄的機制假說，也就是說ATXN8基因有可能因為CAG擴增而轉譯出PolyQ蛋白質；而ATXN8OS基因則是會轉錄出帶有CUG擴增的致病RNA，因此SCA8的致病機制有可能會由蛋白質以及RNA兩種層面而致。為了更進一步了解SCA8致病的分子機制，我們實驗室以大鼠嗜鉻瘤細胞株(PC12)，建立了帶有正常重複範圍(22R)以及不正常擴增(150R)兩種CTG擴增的基因片段的誘導型系統，希望以離體的模式快速觀測ATXNOS基因過度表現會對於神經細胞所產生的影響。從實驗中我們發現帶有致病範圍CTG擴增(150R)的細胞經過誘導基因表現之後，在細胞存活率，以及在神經分化長出的神經突起長度皆有降低的趨勢；除此之外，我們也在細胞內觀察到RNA foci的形成。由這些研究結果，我們可以發現ATXN8OS基因的過度表現會對神經細胞造成傷害，而我們也進一步想研究ATXN8OS基因過度表現是否對於與PC12細胞神經分化有關的一些訊息傳遞路徑造成影響，結果發現經由ATXN8OS基因過度表現所造成的神經分化不良，並非是直接影響其引導神經分化的訊息傳遞路徑，是否和RNA層面alternative splicing有關，進而影響一些調節因子及轉錄因子，則需要進一步相關的研究。

Spinocerebellar ataxia type 8 (SCA8) is an autosomal dominant late-onset neurodegenerative disease. The cause of SCA8 was originally proposed associated with CTG trinucleotide repeat at 3’UTR (untranslated region) of ATXN8OS gene, lying on chromosome 13q21. However, recent studies suggest that bidirectional transcription of ATXN8OS occurs, with its anti-strand, ataxin8 (ATXN8), which encodes a polyQ protein in the CAG orientation, and ATXN8OS transcribed into potentially pathogenic CUG transcripts. SCA8 may thus has both RNA and protein gain of function mechanisms. To understand the molecular pathogenic mechanism of SCA8, we have established inducible PC12 cells with ATXN8OS-22R (normal 22 CTG repeats) or -150R (expanded 150 CTG repeats). Our results show that the viability and neurite outgrowth were significantly reduced in cells with ATXN8OS-150R after induction. Furthermore, the proliferation rate of the cells with ATXN8OS-150R (clones 1 and 4) was obviously decreased by flow cytometry. In addition, the presence of RNA foci was identified in cells with ATXN8OS-22R and -150R. Further investigation in impairment of neurite outgrowth revealed that the neuron differenciation signal transduction pathways of PC12 cells might not be the major targets directly affected by ATXN8OS gene. Whether the mechanism of ATXN8OS gene resulted in hypoplasia of neurite outgrowth related to RNA level associated with alternative splicing needs further investigation.

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。
王薏婷。(2008)。以小鼠及細胞模式探討ATXN8OS過量表現之影響。 台灣師範大學研究所碩士論文。

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