Key Laboratory of Ethnomedicine for Ministry of Education, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing, China.
Schizophr Bull. 2019 Oct 24;45(6):1257-1266. doi: 10.1093/schbul/sby191.
Genetic variants conferring risk for schizophrenia (SCZ) have been extensively studied, but the role of posttranscriptional mechanisms in SCZ is not well studied. Here we performed the first genome-wide microRNA (miRNA) expression profiling in serum-derived exosome from 49 first-episode, drug-free SCZ patients and 46 controls and identified miRNAs and co-regulated modules that were perturbed in SCZ. Putative targets of these SCZ-affected miRNAs were enriched strongly for genes that have been implicated in protein glycosylation and were also related to neurotransmitter receptor and dendrite (spine) development. We validated several differentially expressed blood exosomal miRNAs in 100 SCZ patients as compared with 100 controls by quantitative reverse transcription-polymerase chain reaction. The potential regulatory relationships between several SCZ-affected miRNAs and their putative target genes were also validated. These include hsa-miR-206, which is the most upregulated miRNA in the blood exosomes of SCZ patients and that previously reported to regulate brain-derived neurotrophic factor expression, which we showed reduced mRNA and protein levels in the blood of SCZ patients. In addition, we found 11 miRNAs in blood exosomes from the miRNA sequence data that can be used to classify samples from SCZ patients and control subjects with close to 90% accuracy in the training samples, and approximately 75% accuracy in the testing samples. Our findings support a role for exosomal miRNA dysregulation in SCZ pathophysiology and provide a rich data set and framework for future analyses of miRNAs in the disease, and our data also suggest that blood exosomal miRNAs are promising biomarkers for SCZ.
精神分裂症 (SCZ) 的风险遗传变异已得到广泛研究，但转录后机制在 SCZ 中的作用尚未得到很好的研究。在这里，我们对 49 名首发、未经药物治疗的 SCZ 患者和 46 名对照者的血清衍生外泌体进行了首次全基因组 microRNA (miRNA) 表达谱分析，鉴定了在 SCZ 中受到干扰的 miRNA 和共同调控模块。这些受 SCZ 影响的 miRNA 的假定靶标强烈富集了已被涉及蛋白质糖基化的基因，并且还与神经递质受体和树突 (棘突) 发育有关。我们通过定量逆转录-聚合酶链反应在 100 名 SCZ 患者和 100 名对照者中验证了几种差异表达的血液外泌体 miRNA。还验证了几种受 SCZ 影响的 miRNA 与其假定靶基因之间的潜在调节关系。其中包括 hsa-miR-206，这是 SCZ 患者血液外泌体中上调最明显的 miRNA，之前有报道称其可调节脑源性神经营养因子表达，我们发现 SCZ 患者血液中的 mRNA 和蛋白水平降低。此外，我们从 miRNA 序列数据中发现了 11 种血液外泌体中的 miRNA，这些 miRNA 可用于对 SCZ 患者和对照者的样本进行分类，在训练样本中准确率接近 90%，在测试样本中准确率约为 75%。我们的研究结果支持外泌体 miRNA 失调在 SCZ 病理生理学中的作用，并为未来对该疾病中的 miRNA 进行分析提供了丰富的数据集和框架，并且我们的数据还表明，血液外泌体 miRNA 是 SCZ 的有前途的生物标志物。
