Abstract
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.
Highlights
Brain development is a continuous process which extends from the prenatal period into adulthood (Rapoport et al, 2012)
This study investigated the age-span expression of DAO and DAO activator (DAOA) mRNA and protein in six brain regions of normal human post-mortem brain samples
We determined in silico DNA methylation levels at DAO and DAOA CpG sites in the cerebellum and frontal cortex of control human postmortem brain
Summary
Brain development is a continuous process which extends from the prenatal period into adulthood (Rapoport et al, 2012). Altered gene expression across different brain regions and lifespan has been reported in psychiatric disorders (Sibille, 2013; Darby et al, 2016). NMDA receptors require a co-agonist (glycine or D-serine) binding at the glycine modulatory site in order to function normally. One of the possible explanations for NMDA receptor hypofunction theory proposed in schizophrenia is probably an increased activity of DAO leading to decreased D-serine. DAO activator (DAOA)/G72 ( on addressed as DAOA) binds to DAO, but the effect of DAOA on DAO is controversial This is because DAOA is reported to both increase (Chumakov et al, 2002; Chang et al, 2014) and decrease (Sacchi et al, 2008, 2011) the activity of DAO. The exact function of DAOA is not yet completely understood
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