摘要
MAPT基因是多种神经退行性疾病包括特发性帕金森氏症和阿尔茨海默氏病的危险基因。随着潜在的调节基因表达,我们检测了改变的MAPT基因启动子甲基化在不同病因的阿尔茨海默病患者中是否一种常见的现象。我们通过明确PSEN1基因致病突变的数量来测量早发性阿尔茨海默病(正常= 10, 患者= 10)和特发性晚发型阿尔茨海默病(正常= 12, 患者 = 12)脑组织中MAPT基因启动子的甲基化。我们发现在PSEN1 AD患者中MAPT基因启动子甲基化在大脑特定区域有所减少。体外荧光素酶研究发现PSEN1的过度表达降低MAPT启动子的活性并导致了内源性MAPT基因启动子甲基化增加。荧光素酶实验表明相对于野生型PSEN1,缺失外显子9突变(Δex9)的PSEN1基因的过度表达会导致MAPT基因启动子活性降低,这一结果与调节内源性MAPT基因甲基化能力的下降一致。我们的研究发现了PSEN1对MAP甲基化的新影响以及PSEN1Δex9突变的特异性作用。
关键词: 阿尔茨海默病,DNA甲基化,基因表达,MAPT,突变,PSEN1
Current Alzheimer Research
Title:Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer’s disease
Volume: 12 Issue: 8
Author(s): Kirsten G. Coupland, Woojin S. Kim, Glenda M. Halliday, Marianne Hallupp, Carol Dobson-Stone and John B.J. Kwok
Affiliation:
关键词: 阿尔茨海默病,DNA甲基化,基因表达,MAPT,突变,PSEN1
摘要: The MAPT gene is a risk locus for multiple neurodegenerative diseases, including idiopathic Parkinson’s and Alzheimer’s disease. We examined whether altered DNA methylation of the MAPT promoter, with its potential to modulate gene expression, was a common phenomenon in Alzheimer’s disease patients with differing aetiologies. We measured MAPT promoter methylation in a brain tissue cohort of early-onset Alzheimer’s disease (EOAD) with defined causative mutations in the PSEN1 gene (Normal = 10, PSEN1 AD = 10), and idiopathic late-onset Alzheimer’s disease (Normal = 12, LOAD = 12). We found a brain-region-specific decrease in MAPT promoter methylation in PSEN1 AD patients. Overexpression of PSEN1 reduced MAPT promoter activity in an in vitro luciferase study, and led to an increase in methylation of the endogenous MAPT promoter. Overexpression of PSEN1 with a deletion of exon 9 mutation (Δex9) led to a smaller reduction in MAPT promoter activity relative to wild-type PSEN1 in the luciferase assay, consistent with a decreased ability to modulate endogenous MAPT gene methylation. Our study indicates a novel effect of PSEN1 on MAPT methylation, and suggests a mutation-specific effect of the PSEN1 Δex9 mutation.
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Cite this article as:
Coupland G. Kirsten, Kim S. Woojin, Halliday M. Glenda, Hallupp Marianne, Dobson-Stone Carol and Kwok B.J. John, Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer’s disease, Current Alzheimer Research 2015; 12 (8) . https://dx.doi.org/10.2174/1567205012666150710110756
DOI https://dx.doi.org/10.2174/1567205012666150710110756 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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