Expression of D-Amino Acid Oxidase (DAO/DAAO) and D-Amino Acid Oxidase Activator (DAOA/G72) during Development and Aging in the Human Post-mortem Brain.
Expression of D-Amino Acid Oxidase (DAO/DAAO) and D-Amino Acid Oxidase Activator (DAOA/G72) during Development and Aging in the Human Post-mortem Brain.
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DOI：
10.3389/fnana.2017.00031
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发表时间：
2017
影响因子：
2.9
通讯作者：
Grünblatt E
中科院分区：
文献类型：
--
作者：
Jagannath V;Marinova Z;Monoranu CM;Walitza S;Grünblatt E
在大脑中，D-氨基酸氧化酶 (DAO/DAAO) 主要氧化 D-丝氨酸，它是 N-甲基-D-天冬氨酸 (NMDA) 受体的共同激动剂。因此，DAO 可以通过 D-丝氨酸分解来调节 NMDA 受体的功能。此外，DAO 激活剂 (DAOA)/G72 已被报道为 DAOA 和阻抑剂。 DAO 和 DAOA 基因和蛋白质在人脑中的共表达尚未阐明。本研究的目的是了解 DAO 和 DAOA（mRNA 和蛋白质）的区域和年龄跨度分布。我们使用定量实时逆转录聚合酶链反应和酶联免疫吸附测定测定了正常人死后大脑样本（妊娠 16 周至 91 岁）中六个大脑区域的 DAO 和 DAOA mRNA 和蛋白质表达。我们发现，与研究的其他大脑区域相比，小脑中 DAO mRNA 的表达量较高，而小脑中 DAO 蛋白的表达量较低，这表明存在转录后调节。我们在所有研究的大脑区域中检测到了 DAOA 蛋白，但没有检测到 DAOA mRNA，这表明表达受到严格调控。为了了解转录水平上的这种调控，我们分析了从基因表达综合数据集中获得的对照人死后大脑的小脑和额叶皮层中 DAO 和 DAOA CpG 位点的 DNA 甲基化水平。事实上，小脑中的 DAO 和 DAOA CpG 位点比额叶皮层中的 DAO 和 DAOA CpG 位点显着更加甲基化。在研究寿命影响时，我们发现小脑和杏仁核中 DAO mRNA 水平与年龄 <2 岁呈正相关。我们还在除额叶皮层之外的所有研究的大脑区域中检测到 DAO 和 DAOA 蛋白之间存在显着的正相关性（控制年龄）。总之，人脑中 DAO 和 DAOA 的表达均依赖于年龄和大脑区域。
In the brain, D-amino acid oxidase (DAO/DAAO) mainly oxidizes D-serine, a co-agonist of the N-methyl-D-aspartate (NMDA) receptors. Thus, DAO can regulate the function of NMDA receptors via D-serine breakdown. Furthermore, DAO activator (DAOA)/G72 has been reported as both DAOA and repressor. The co-expression of DAO and DAOA genes and proteins in the human brain is not yet elucidated. The aim of this study was to understand the regional and age span distribution of DAO and DAOA (mRNA and protein) in a concomitant manner. We determined DAO and DAOA mRNA and protein expression across six brain regions in normal human post-mortem brain samples (16 weeks of gestation to 91 years) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. We found higher expression of DAO mRNA in the cerebellum, whereas lower expression of DAO protein in the cerebellum compared to the other brain regions studied, which suggests post-transcriptional regulation. We detected DAOA protein but not DAOA mRNA in all brain regions studied, suggesting a tightly regulated expression. To understand this regulation at the transcriptional level, we analyzed DNA methylation levels at DAO and DAOA CpG sites in the cerebellum and frontal cortex of control human post-mortem brain obtained from Gene Expression Omnibus datasets. Indeed, DAO and DAOA CpG sites in the cerebellum were significantly more methylated than those in the frontal cortex. While investigating lifespan effects, we found that DAO mRNA levels were positively correlated with age <2 years in the cerebellum and amygdala. We also detected a significant positive correlation (controlled for age) between DAO and DAOA protein in all of the brain regions studied except for the frontal cortex. In summary, DAO and DAOA expression in the human brain are both age and brain region dependent.