PPP2R2B (Bβ) 為廣泛表現在腦部的去磷酸酶 PP2A 的調控次單位。PPP2R2B 基因啟動子的差異使用及選擇性裁接，產生 Bβ1 及Bβ2 兩種異構型。Bβ1 異構型基因 5' 端的 CAG 重複擴增會使 Bβ1 的表現量增加，而導致第十二型脊髓小腦運動失調症。反之，本實驗室先前研究成果顯示，罕見短的 (CAG)5~7 等位基因和低轉錄活性及阿茲海默氏症相關。此外，外遺傳調控及功能性單一鹼基多型性等因子亦可能影響 Bβ1 的表現量。為檢視 Bβ1 基因 5' 端的外遺傳變化，我們以阿茲海默氏症病患及正常人的血液或淋巴細胞株 DNA 為材料，利用限制酶為基礎的甲基化試驗及 bisulfite 定序，來評估 CpG 島的甲基化程度，並利用染色質沉澱-聚合酶鏈鎖反應試驗，來評估染色質結構。結果發現阿茲海默氏症患者的 DNA 甲基化程度及組蛋白 dimethyl H3-K9 比值的增加，顯示外遺傳的變化可能改變阿茲海默氏症患者的 Bβ1 基因表現。在阿茲海默氏症與正常人族群的病例-對照組分析方面，我們檢測了 6 個 Bβ1 異構型基因啟動子上的單一鹼基多型性，與阿茲海默氏症、血管性失智症感受性的相關性。結果發現各多型性基因型、等位基因或單套型在患者與正常人族群間沒有顯著差異。最後本論文延續先前研究，擴大 Bβ1 異構型基因 CAG 三核苷酸重複的遺傳資料庫。雖然並未發現擴增的等位基因，但於二位舞蹈症患者中，觀察到罕見短的 (CAG)4 與 (CAG)6 等位基因，顯示此低轉錄活性的罕見短的等位基因可能與國人的舞蹈症相關。

PPP2R2B (Bβ) is an important regulator of protein phosphatase 2A activity in the brain. Through differential promoter usage and alternative splicing, two major isoforms Bβ1 and Bβ2 are produced. Increased expression of the abundant Bβ1 isoform due to CAG repeat expansion causes autosomal dominant spinocerebellar ataxia type 12. Contrarily, our case-control study and reporter assay indicated that the rare short 5~7 triplet alleles are associated with decreased transcriptional activity and Alzheimer's disease (AD). In addition to the CAG repeat variation on Bβ1 expression, the epigenetic change and functional single nucleotide polymorphisms may also alter the Bβ1 expression. To examine this, restriction enzyme based-methylation assay and bisulfite sequencing were used to assess the CpG methylation and ChIP-PCR assay to assess the chromatin structure using lymphocyte or lymphoblastoid DNA from AD patients and controls. The results of increased DNA methylation and dimethyl H3-K9 ratio in the 5' region of Bβ1 gene suggest that the epigenetic change may alter the Bβ1 expression in AD patients. In addition, a case-control study was conducted to investigate the association of six Bβ1 promoter single nucleotide polymorphisms (SNPs) with the risk of AD or vascular dementia. No significant difference in genotype, allele and haplotype frequency distribution between cases and controls was observed. Finally, we screened the Bβ1 CAG repeats distribution in normal controls and in patients with various neurodegenerative diseases. No expanded allele was found in either group. However, the rare short (CAG)4 and (CAG)6 alleles were observed in two patients with chorea. As rare short triplet alleles give rise to a significant decrease in the expression level, the results suggest the involvement of rare short triplet alleles with chorea.

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