第八型脊髓小腦運動失調症：ATXN8基因啟動子上多型性點之遺傳與功能性分析研究

Abstract

第八型脊髓小腦運動失調症(簡稱SCA8)是一種會導致小腦運動能力失調的體染色體顯性遺傳之神經退化性疾病，但是其外顯率並不完全。SCA8相關基因是在染色體13q21的位置，包含了ATXN8OS CUG重複擴增RNA及ATXN8多麩醯胺(polyQ)擴增的蛋白。先前本實驗室研究SCA8重複序列在台灣人族群中的分佈情形，結果發現在巴金森氏症族群中的等位基因的比例較正常人族群高(8/593=1.3%相較於3/659=0.2%)，雖然未達顯著性(Wu et al., 2009)。另外，我們在ATXN8的啟動子上發現一新穎的-62 G/A多型性，神經腫瘤細胞及胚胎腎細胞的螢光酵素報告檢測顯示，包含-62G等位基因的啟動子轉錄活性顯著高於-62A等位基因(Wu et al., 2009)。本論文探討-62 G/A多型性對帕金森氏症感受性與分子機轉。首先針對此多型性點進行帕金森氏症患者及性別、年齡相當的正常人族群的病例-對照組研究，結果發現AA基因型者有顯著低的疾病罹患風險。其次探究-62 G/A多型性對ATXN8基因的啟動子調控，cDNA過度表現及luciferase reporter檢測顯示在SK-N-SH細胞中，轉錄因子C/EBPA會增強ATXN8啟動子的活性，但CEBPA與ATXN8 -62G、-62A啟動子的結合檢測，並未看出顯著的差異。

Spinocerebellar ataxia type 8 (SCA8) is a hereditary neurodegenerative disorder, manifesting itself as a slowly progressive cerebellar ataxia. The penetrance of SCA8 is incomplete. SCA8 involves the expression of a CTG/CAG expansion mutation from opposite strands producing CUG expansion transcripts (ATXN8OS) and a polyglutamine expansion protein (ATXN8) on chromosome 13q21 known to be pathogenic on other disorders. Previously we assessed the SCA8 repeat size ranges in Taiwanese population and found an increase (although not significant) in the proportion of the individuals carrying SCA8 larger alleles in Parkinson’s disease (PD) (8/593=1.3%) as compared to that in the control subjects (3/659=0.2%) (Wu et al., 2009). In addition, a novel -62 G/A promoter SNP was identified with significantly higher transcriptional activity in the luciferase reporter construct containing the -62G allele than that containing the -62A allele in both neuroblastoma and embryonic kidney cells (Wu et al., 2009). The purpose of this study is to investigate the ATXN8 -62 G/A polymorphism and the risk of Parkinson's disease using a case-control study. The results demonstrate that individuals carrying AA genotype exhibited a decrease risk of Taiwanese PD. cDNA over-expression and luciferase reporter assay revealed that CEBPA binds to the ATXN8 proximal promoter to up-regulate ATXN8 expression in neuroblastoma SK-N-SH cells. Nevertheless, no significant difference was observed upon examining the binding of CEBPA to ATXN8 -62G、-62A.