Coupland Kirsten G, Kim Woojin S, Halliday Glenda M, Hallupp Marianne, Dobson-Stone Carol, Kwok John B J
Neuroscience Research Australia, Barker St, Randwick, NSW, Australia.
Curr Alzheimer Res. 2015;12(8):745-51. doi: 10.2174/1567205012666150710110756.
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.
微管相关蛋白tau（MAPT）基因是多种神经退行性疾病的风险基因座，包括特发性帕金森病和阿尔茨海默病。我们研究了MAPT启动子DNA甲基化改变（其具有调节基因表达的潜力）在病因不同的阿尔茨海默病患者中是否是一种常见现象。我们在一个脑组织队列中测量了MAPT启动子甲基化情况，该队列包括早发性阿尔茨海默病（EOAD）患者（PSEN1基因存在明确致病突变，正常组 = 10例，PSEN1突变型阿尔茨海默病组 = 10例）以及散发性晚发性阿尔茨海默病患者（正常组 = 12例，LOAD组 = 12例）。我们发现PSEN1突变型阿尔茨海默病患者的MAPT启动子甲基化存在脑区特异性降低。在体外荧光素酶研究中，PSEN1过表达降低了MAPT启动子活性，并导致内源性MAPT启动子甲基化增加。与野生型PSEN1相比，PSEN1外显子9缺失突变体（Δex9）过表达在荧光素酶测定中导致MAPT启动子活性降低幅度较小，这与调节内源性MAPT基因甲基化能力下降一致。我们的研究表明PSEN1对MAPT甲基化有新的作用，并提示PSEN1 Δex9突变存在突变特异性效应。
