脊髓小腦運動失調症(Spinocerebellar ataxias, SCAs)是一群體染色體顯性遺傳的神經退化性疾病，小腦功能異常是所有類型的共同症狀，且其中許多類型亦會引起中樞或是周邊神經系統的損傷。第十二型脊髓小腦運動失調症(SCA12)為PPP2R2B基因5'端CAG三核重複擴增的疾病。PPP2R2B基因會轉譯出一個專一表現在腦部的去磷酸PP2A (protein phosphotase 2A)的調控次單位Bβ，來調節PP2A對vimentin、histone-1、tau等蛋白的去磷酸化活性。本研究的目的在探討PPP2R2B基因CAG三核重複的遺傳及功能性角色。本研究分析了阿茲海默氏症、帕金森式氏症、運動失調症、精神病患者及正常人族群的PPP2R2B基因CAG三核重複的分佈頻率，發現CAG三核酸重複範圍沒有顯著差別，但阿茲海默氏症樣品群的(CAG)7的比例顯著高於其他樣品群。人類腦癌細胞株SK-N-SH、LA-N-1、IMR-32、胚胎腎細胞HEK-293及大鼠ST14A細胞的啟動子功能性分析顯示，CAG三核上游序列而非下游序列的缺失，會減低其啟動子活性。CAG三核重複的擴增(49及64個三核)會使PPP2R2B基因啟動子活性增加二至三倍，但罕見的(CAG)7 對偶基因表現的活性，僅為族群中常見的10、13、16個三核對偶基因的60%。CAG重複的變異可能影響鄰近啟動子element的相對距離，進而影響其啟動子活性。PPP2R2B基因啟動子(CAG)7 對偶基因可能為一功能性的多型性，影響個體對阿茲海默氏症的感受性。

The hereditary spinocerebellar ataxias (SCAs) are a group of autosomal dominant adult onset neurodegenerative disorders. Cerebellar dysfunction is a hallmark of all the SCAs, and most also involve other regions of the central or peripheral nervous system. SCA12 is caused by a CAG repeat expansion in the 5' UTR of the PPP2R2B gene. The PPP2R2B gene encodes a brain-specific regulatory subunit Bβ of PP2A (protein phosphotase 2A). Bβ regulates PP2A dephosphorylation activity for specific substrates, including vimentin, histone-1, and tau. The purpose of this study was to determine the genetic and functional roles of the CAG repeat polymorphism within the PPP2R2B gene. The CAG repeat was analyzed in patients with Alzheimer's disease, Parkinson's disease, ataxia, schizophrenia, and healthy controls. The distribution of the alleles in patients was not significantly different from that in the controls, whereas the (CAG)7 allele was significantly overrepresented in the AD patients compared to the controls. The promoter functional assay showed that the deletion of the upstream sequence, but not the downstream sequence of the CAG repeat, reduced the PPP2R2B promoter activity. Expansions of the repeat (49 and 64 triplets) caused a 2~3-fold increase in PPP2R2B promoter activity and the rare (CAG)7 allele displayed 60% activity, as compared to the common 10-, 13-, and 16-triplet alleles, respectively, in human SK-N-SH, LA-N-1, IMR-32, HEK-293 and rat ST14A cells. The upstream sequence of the CAG repeat, but not the CAG repeat or its downstream sequence, was essential for the PPP2R2B transcription. Variations in the CAG repeat number may alter the spacing of flanking promoter elements to influence the expression of PPP2R2B. The (CAG)7 may be a functional polymorphism in the 5' promoter region of PPP2R2B and may be associated with the susceptibility to AD.

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