| 1 | PLoS ONE 2007 -1 2: e873 |
|---|---|
| PMID | 17849003 |
| Title | Brain expressed microRNAs implicated in schizophrenia etiology. |
| Abstract | Protein encoding genes have long been the major targets for research in精神分裂症genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for精神分裂症-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation. We have studied the association between精神分裂症and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257精神分裂症patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to精神分裂症in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 andTAF1连接在紧密的网络中。JUN和两个网络中的两个miRNA靶标（CCND2和PTPN1）以前已与精神分裂症。 We found nominal association between brain-expressed miRNAs and精神分裂症for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors. |
| SCZ关键字 | 精神分裂症 |
| 2 | Arch. Toxicol. 2009 Aug 83: 747-62 |
| PMID | 19212759 |
| Title | D-Serine exposure resulted in gene expression changes implicated in neurodegenerative disorders and neuronal dysfunction in male Fischer 344 rats. |
| Abstract | D-丝氨酸是一种内源性氨基酸，通过与N-甲基-D-天冬氨酸（NMDA）受体的甘氨酸结合位点的相互作用参与许多生理过程。它在开发，学习和细胞死亡信号传导中具有重要作用。最近的证据表明，NMDA受体的功能降低与病因有关精神分裂症, and the use of D-serine as add-on therapy is beneficial in alleviating the symptoms of treatment-refractory精神分裂症。NMDA受体在缺血，癫痫和创伤的兴奋性氨基酸毒性介导的神经元细胞死亡和神经变性中也起着重要作用。由于其共激活因子功能，D丝氨酸可以显着增强NMDA介导的兴奋性毒性。为了研究D丝氨酸治疗的潜在不良反应，我们研究了用单次腹膜内注射D丝氨酸治疗的雄性F-344大鼠前脑的基因表达变化（5、20、50、200或500 mg/kg）治疗后96小时。使用Affymetrix大鼠基因组230 2.0阵列进行基因表达谱分析表明，基于使用三种统计方法鉴定的常见基因，D-丝氨酸治疗分别导致134和52基因的上调和下调134和52基因（p <0.01）（p <0.01超过两次连续剂量），方差分析（进行多次测试的Bonferonni校正）和微阵列的显着性分析（SAM）。差异表达基因的自组织图（SOM）聚类分析显示两个簇，一个簇，所有134个上调的探针集，另一个带有所有52个下调的探针集。下调簇的剂量反应模式几乎显示出上调的镜像的完美镜像。基因本体分析表明，与神经元功能和/或神经退行性疾病有关的途径在差异表达的基因之间过多代表。 Specifically, genes involved in vesicle-mediated transport, endocytosis, ubiquitin conjugation pathway, regulation of actin filament polymerization/depolymerization, focal adhesion, Wnt signaling, and insulin signaling were up-regulated, while genes involved in RNA metabolism/splicing/processing and Notch signaling were down-regulated. Consistent with this finding, pathway analysis using GenMAPP showed a significant number of differentially expressed genes in these pathways. In addition, the GenMAPP result also showed activation of the signaling pathways of several proinflammatory cytokines (including IL-2, IL-3, IL-5, IL-6 and TNF-alpha), which might suggest the onset of neuroinflammation. Biological association network analysis showed that several nuclear factors implicated in transcription regulation (includingTAF1, Max, Myc, and Hnf4a) are highly connected to a large number of up-regulated genes. While the transcript levels of these transcription factors were not changed, their connections to Ddx3x, a gene involved in mRNA processing and translation initiation, raise the possibility that they may be up-regulated at the post-transcriptional level. The observation that Ubqln1 and Ube2d, two differentially expressed genes involved in ubiquitin-mediated proteolysis and implicated in neurodegenerative disorders, are highly connected in this network suggests a role of ubiquitination proteasome pathway in response to D-serine exposure. This finding is consistent with the result of gene ontology analysis and suggests that D-serine treatment might result in damage to cellular proteins and subsequent up-regulation of ubiquitination proteasome pathway to clear these damaged proteins. In summary, D-serine exposure resulted in perturbation of a number of pathways implicated in neuronal functions and neurodegenerative disorders. However, activation of cellular response to counter the toxic effects of D-serine might be hindered due to the down-regulation of such important cellular machinery like RNA metabolism, splicing and processing. Consequently, cell damage might be further exacerbated. Taken together, these findings highlight the potential impacts of D-serine exposure on neuronal functions. |
| SCZ关键字 | 精神分裂症 |