McGill Group for Suicide Studies, Douglas Hospital Research Institute, McGill University, Montreal, Quebec, Canada.
PLoS One. 2012;7(6):e39301. doi: 10.1371/journal.pone.0039301. Epub 2012 Jun 25.
TrkB-T1 is a BDNF receptor lacking a tyrosine kinase domain that is highly expressed in astrocytes and regulates BDNF-evoked calcium transients. Previous studies indicate that downregulation of TrkB-T1 in frontal cortex may be involved in neurobiological processes underlying suicide.
In a microarray screening study (N = 8), we interrogated all known microRNA in the frontal cortex of suicide completers with low expression of TrkB-T1 and normal controls. These findings were validated and followed up in a larger sample of cases and controls (N = 55). Functional analyses included microRNA silencing, microRNA overexpression and luciferase assays to investigate specificity and to validate interactions between differentially expressed microRNA and TrkB-T1.
MicroRNAs Hsa-miR-185* and Hsa-miR-491-3p were upregulated in suicide completers with low expression of TrkB.T1 (P(nominal): 9.10(-5) and 1.8.10(-4) respectively; FDR-corrected p = 0.031). Bioinformatic analyses revealed five putative binding sites for the DiGeorge syndrome linked microRNA Hsa-miR-185in the 3'UTR of TrkB-T1, but none for Hsa-miR-491-3P. The increase of Hsa-miR-185 in frontal cortex of suicide completers was validated then confirmed in a larger, randomly selected group of suicide completers, where an inverse correlation between Hsa-miR-185* and TrkB-T1 expression was observed (R = -0.439; p = 0.001). Silencing and overexpression studies performed in human cell lines confirmed the inverse relationship between hsa-mir-185* and trkB-T1 expression. Luciferase assays demonstrated that Hsa-miR-185* binds to sequences in the 3'UTR of TrkB-T1.
These results suggest that an increase of Hsa-miR-185* expression levels regulates, at least in part, the TrkB-T1 decrease observed in the frontal cortex of suicide completers and further implicate the 22q11 region in psychopathology.
TrkB-T1 是一种 BDNF 受体，缺乏酪氨酸激酶结构域，在星形胶质细胞中高度表达，并调节 BDNF 诱发的钙瞬变。先前的研究表明，前额叶皮质中 TrkB-T1 的下调可能与自杀的神经生物学过程有关。
在一项微阵列筛选研究（N=8）中，我们检测了低表达 TrkB-T1 的自杀未遂者和正常对照者前额叶皮质中的所有已知 microRNA。这些发现通过在更大的病例和对照样本（N=55）中进行验证和跟进得到证实。功能分析包括 microRNA 沉默、microRNA 过表达和荧光素酶测定，以研究特异性，并验证差异表达的 microRNA 与 TrkB-T1 之间的相互作用。
在低表达 TrkB-T1 的自杀未遂者中，miR-185和 miR-491-3p 上调（P（名义）：9.10（-5）和 1.8.10（-4），分别；经 FDR 校正的 p=0.031）。生物信息学分析显示，在 TrkB-T1 的 3'UTR 中有五个可能的 DiGeorge 综合征相关 microRNA Hsa-miR-185结合位点，但没有 Hsa-miR-491-3P 的结合位点。在自杀未遂者的前额叶皮质中验证了 Hsa-miR-185的增加，随后在更大的、随机选择的自杀未遂者组中得到证实，其中观察到 Hsa-miR-185和 TrkB-T1 表达之间存在负相关（R=-0.439；p=0.001）。在人细胞系中进行的沉默和过表达研究证实了 hsa-mir-185和 trkB-T1 表达之间的负相关关系。荧光素酶测定表明，Hsa-miR-185结合到 TrkB-T1 3'UTR 的序列上。
这些结果表明，Hsa-miR-185*表达水平的增加至少部分调节了自杀未遂者前额叶皮质中观察到的 TrkB-T1 减少，并进一步表明 22q11 区域与精神病理学有关。
