Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany; Microarray Core Unit, IZKF Würzburg, University Hospital of Würzburg, Germany.
Department of Pharmacology, The Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden.
Eur Neuropsychopharmacol. 2014 Jan;24(1):65-85. doi: 10.1016/j.euroneuro.2013.09.005. Epub 2013 Sep 27.
NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia.
NO 是一种多效信号分子，在认知和情绪中具有重要作用。在大脑中，NO 由神经元型一氧化氮合酶（NOS-I，由 NOS1 编码）通过 PDZ 相互作用与 NMDA 受体偶联产生；这种蛋白质-蛋白质相互作用在 NOS1 衔接蛋白（由 NOS1AP 编码）与 NOS-I 结合时被破坏。由于 NOS1 和 NOS1AP 都与精神分裂症有关，我们在这里通过对新样本进行基因分型并对我们自己和已发表的数据进行荟萃分析，更详细地研究了这些基因。这样，我们确认了这两个基因与精神分裂症的关联，并发现了它们相互作用增加疾病风险的证据。我们最强有力的发现是 NOS1 启动子 SNP rs41279104，荟萃分析的优势比为 1.29。由于异源细胞系统的研究结果表明，风险等位基因降低了基因表达，我们研究了该变体对人类死后大脑样本中 NOS1 表达的影响，发现风险等位基因显著降低了前额叶皮质中 NOS1 的表达。生物信息学分析表明，这可能是由于替代了六个转录因子结合位点，导致两个新的结合位点作为代理 SNP 的结果。总之，我们的数据表明，NOS1 中的遗传变异导致该基因在前额叶脑中的表达降低，导致精神分裂症易感性，并且 NOS1 与 NOS1AP 相互作用。因此，NOS1-NOS1AP PDZ 界面很可能成为至少某些形式精神分裂症中小分子的新靶标。
