PPP2R2B基因轉譯出一個專一表現在腦部的去磷酸酶PP2A的調控次單位Bβ。當PPP2R2B基因5’端CAG三核苷酸不正常擴增時，會造成第十二型脊髓小腦運動失調症(SCA12)，但當抑制PP2A活性時，會使動物腦部Tau蛋白過度磷酸化，出現類阿茲海默氏症的症狀。先前本實驗室研究顯示，PPP2R2B基因上游-870 ~ +23序列可調節基因基礎表現，且台灣阿茲海默氏症患者中PPP2R2B基因5’端啟動子活性較低的(CAG)7等位基因頻率較正常人族群為高(2.8% vs. 0.2%)。本論文延續先前研究，首先擴大正常人及神經性疾病患者PPP2R2B基因CAG三核苷重複的遺傳資料庫，未發現任何擴增的等位基因，但在4位原發性顫抖症(2.0%)及1位舞蹈症(1.1%)患者，觀察到短的(CAG)5~7等位基因。其次分析PPP2R2B基因4 kb啟動子片段上4個單一鹼基多型性與阿茲海默氏症、原發性顫抖症感受性的相關性，各多型性基因型或等位基因在患者與正常人族群間沒有顯著差異，但-3170C/-2923A/-1905T/-428G單套型可能與阿茲海默氏症的感受性相關。在HEK-293、IMR-32細胞中，-4070 ~ +23的遠端啟動子的轉錄活性顯著低於-870 ~ +23近端啟動子，在SK-N-SH、HEK-293、IMR-32細胞中，(CAG)5~7的近端啟動子轉錄活性亦顯著低於(CAG)16者。

PPP2R2B is a brain-specific regulatory B subunit of protein phosphatase 2A (PP2A), whose activity is shown to be relevant to Alzheimer’s disease (AD) and other tauopathy. PP2A is a major serine/ threonine phosphatase expressed in all eukaryotic cells. It has been suggested that increased PPP2R2B expression due to CAG repeat expansion at the 5’end of the gene may result in spinocerebellar ataxia 12. However, when the expression of PP2A was suppressed, tau protein was hyper-phosphorylated in the brain, which may result in pathology like AD. We screened the PPP2R2B gene CAG repeats distribution in normal controls and in patients with various neurodegenerative diseases. The distribution of the alleles in cases did not differ significantly from that in the controls, and no expanded allele was found in either groups. However, the shorter (CAG)5~7 alleles were over-represented in patients with tremor (2.0%) and chorea (1.1%) compared with that in the controls (0.0%). In addition, a case-control study was conducted to investigate the association of four PPP2R2B promoter single nucleotide polymorphisms (SNPs) with the risk of AD or tremor. Again no significant difference in genotype and allele frequency distribution between cases and controls was observed. However, the more frequent -3170C/-2923A/-1905T/ -428G haplotype was evidently associated with AD (P = 0.019, odds ratio: 5.99; 95% CI: 1.64-38.4). The 4-kb distal fragment displayed significant decrease promoter activity compared to the 0.9-kb proximal fragment in both IMR-32 (85% activity, P = 0.014) and HEK-293 cells (82% activity, P = 0.013). Compared to the common 16-triplet allele, the rare 5~7-triplet alleles give rise to a significant decrease in the expression level in SK-N-SH, IMR-32 and HEK-293 (0.41~0.79, P = 0.000~0.040).

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