Department of Neurosciences, University of Toledo, Toledo, OH, USA.
Department of Neurosciences, University of Toledo, Toledo, OH, USA.
Schizophr Res. 2022 Nov;249:38-46. doi: 10.1016/j.schres.2020.03.018. Epub 2020 Mar 17.
Altered expression and localization of the glutamate transporter EAAT2 is found in schizophrenia and other neuropsychiatric (major depression, MDD) and neurological disorders (amyotrophic lateral sclerosis, ALS). However, the EAAT2 interactome, the network of proteins that physically or functionally interact with EAAT2 to support its activity, has yet to be characterized in severe mental illness. We compiled a list of "core" EAAT2 interacting proteins. Using Kaleidoscope, an R-shiny application, we data mined publically available postmortem transcriptome datasets to determine whether components of the EAAT2 interactome are differentially expressed in schizophrenia and, using Reactome, identify which interactome-associated biological pathways are altered. Overall, these "look up" studies highlight region-specific, primarily frontal cortex (dorsolateral prefrontal cortex and anterior cingulate cortex), changes in the EAAT2 interactome and implicate altered metabolism pathways in schizophrenia. Pathway analyses also suggest that perturbation of components of the EAAT2 interactome in animal models of antipsychotic administration impact metabolism. Similar changes in metabolism pathways are seen in ALS, in addition to altered expression of many components of the EAAT2 interactome. However, although EAAT2 expression is altered in a postmortem MDD dataset, few other components of the EAAT2 interactome are changed. Thus, "look up" studies suggest region- and disease-relevant biological pathways related to the EAAT2 interactome that implicate glutamate reuptake perturbations in schizophrenia, while providing a useful tool to exploit "omics" datasets.
谷氨酸转运体 EAAT2 的表达和定位在精神分裂症和其他神经精神疾病（重度抑郁症，MDD）和神经退行性疾病（肌萎缩侧索硬化症，ALS）中发生改变。然而，EAAT2 相互作用组，即与 EAAT2 物理或功能相互作用以支持其活性的蛋白质网络，在严重精神疾病中尚未得到描述。我们编制了一份“核心”EAAT2 相互作用蛋白清单。使用 Kaleidoscope，一个 R-shiny 应用程序，我们对公开的尸检转录组数据集进行数据挖掘，以确定 EAAT2 相互作用组的成分是否在精神分裂症中表达不同，并且使用 Reactome 来确定哪些相互作用组相关的生物途径发生改变。总体而言，这些“查找”研究强调了 EAAT2 相互作用组的区域特异性变化，主要是前额叶皮层（背外侧前额叶皮层和前扣带皮层），并暗示精神分裂症中代谢途径发生改变。通路分析还表明，在抗精神病药物给药的动物模型中，EAAT2 相互作用组成分的扰动会影响代谢。在 ALS 中还观察到代谢途径的类似变化，此外，EAAT2 相互作用组的许多成分的表达也发生改变。然而，尽管在 MDD 尸检数据集中改变了 EAAT2 的表达，但 EAAT2 相互作用组的其他几个成分并未改变。因此，“查找”研究表明与 EAAT2 相互作用组相关的与疾病相关的区域生物学途径，暗示谷氨酸再摄取扰动与精神分裂症有关，同时为利用“组学”数据集提供了有用的工具。
