DNA Methylation of Alzheimer Disease and Tauopathy-Related Genes in Postmortem Brain
DNA Methylation of Alzheimer Disease and Tauopathy-Related Genes in Postmortem Brain
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DOI：
10.1097/nen.0b013e3181af2e46
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发表时间：
2009-08-01
影响因子：
3.2
通讯作者：
Ferrer, Isidre
中科院分区：
文献类型：
--
作者：
Barrachina, Marta;Ferrer, Isidre
DNA甲基化主要发生在二核苷酸CpG位点的鸟嘌呤之前的胞嘧啶上；它是正常发育过程中表观遗传DNA调节和癌症中异常DNA的最重要机制之一。为了确定在死后人类大脑中进行DNA甲基化研究的可行性，我们评估了不同死后人为增加延迟长达48小时的大脑样本。分析了对照组(n=26)和阿尔茨海默病I~II期患者(n=17)额叶皮质和海马区MAPT、APP和PSEN1特定区域的DNA甲基化情况：阿尔茨海默病III~IV期15例；阿尔茨海默病V~VI期12例；嗜银颗粒病10例；与tau突变有关的额颞叶变性6例；额颞叶变性伴泛素免疫反应阳性包涵体4例；额颞叶变性伴运动神经元疾病3例；Pick病(n=3)：帕金森病(n=8)，路易体痴呆(n=5)，路易体痴呆(n=15)。对正常对照组和帕金森病及相关联核病患者的额叶皮质UCHL1基因进行分析。DNA甲基化位点在每个病例中都具有很高的重复性。在对照和疾病样本之间，或者在所分析的任何地区的不同病理实体之间，没有发现CpG甲基化百分比的差异。因为脆弱细胞中DNA启动子甲基化的微小变化可能在总匀浆中没有检测到。然而，应谨慎解读这些结果，特别是当它们与慢性退行性疾病有关时，在这些疾病中，微小的修改可能足以调节疾病的进展。
DNA methylation Occurs predominantly at cytosines that precede guanines in dinucleotide CpG sites; it is one of the most important mechanisms for epigenetic DNA regulation during normal development and for aberrant DNA in cancer. To determine the feasibility of DNA methylation studies in the Postmortem human brain, we evaluated brain samples with variable Postmortem artificially increased delays up to 48 hours. DNA methylation was analyzed in selected regions of MAPT, APP, and PSEN1 in the frontal cortex and hippocampus of controls (n = 26) and those with Alzheimer disease at Stages I to II (n = 17): Alzheimer disease at Stages III to IV (n = 15); Alzheimer disease at Stages V to VI (n = 12); argyrophilic grain disease (n = 10); frontotemporal lobar degeneration linked to tau Mutations (n = 6) frontotemporal lobar degeneration with ubiquitin-immunoreactive re inclusions (n = 4); frontotemporal lobar degeneration with motor neuron disease (n = 3); Pick disease (n = 3): Parkinson disease (n = 8); dementia with Lewy bodies., pure form (n = 5): and dementia with Lewy bodies, common form (n = 15). UCHL1 (ubiquitin carboxyl-terminal hydrolase 1 gene) was analyzed in the frontal cortex of controls and those with Parkinson disease and related synucleinopathies. DNA methylation sites were very reproducible in every case. No differences in the percentage of CpG methylation were found between control and disease samples or among the different pathological entities in any region analyzed. Because small changes in methylation of DNA promoters in vulnerable cells might have not been detected in total homogenates. however, these results should be interpreted with caution, particularly as they relate to chronic degenerative diseases in which small modifications may be sufficient to modulate disease progression.