Protein kinases orchestrate signal transduction pathways involved in central nervous system functions ranging from neurodevelopment to synaptic transmission and plasticity. Abnormalities in kinase-mediated signaling are involved in the pathophysiology of neurological disorders, including neuropsychiatric disorders. Here, we expand on the hypothesis that kinase networks are dysregulated in schizophrenia. We investigated changes in serine/threonine kinase activity in cortical excitatory neurons differentiated from induced pluripotent stem cells (iPSCs) from a schizophrenia patient presenting with a 4 bp mutation in the disrupted in schizophrenia 1 (DISC1) gene and a corresponding control. Using kinome peptide arrays, we demonstrate large scale abnormalities in DISC1 cells, including a global depression of serine/threonine kinase activity, and changes in activity of kinases, including AMP-activated protein kinase (AMPK), extracellular signal-regulated kinases (ERK), and thousand-and-one amino acid (TAO) kinases. Using isogenic cell lines in which the DISC1 mutation is either introduced in the control cell line, or rescued in the schizophrenia cell line, we ascribe most of these changes to a direct effect of the presence of the DISC1 mutation. Investigating the gene expression signatures downstream of the DISC1 kinase network, and mapping them on perturbagen signatures obtained from the Library of Integrated Network-based Cellular Signatures (LINCS) database, allowed us to propose novel drug targets able to reverse the DISC1 kinase dysregulation gene expression signature. Altogether, our findings provide new insight into abnormalities of kinase networks in schizophrenia and suggest possible targets for disease intervention.

中文翻译：

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人诱导的DISC1精神分裂症多能干细胞模型中的激酶网络失调。

蛋白激酶协调参与中枢神经系统功能的信号转导途径，范围从神经发育到突触传递和可塑性。激酶介导的信号传导异常与神经系统疾病（包括神经精神疾病）的病理生理有关。在这里，我们扩大了在精神分裂症中激酶网络失调的假说。我们研究了从精神分裂症患者的诱导多能干细胞（iPSC）分化出来的皮质兴奋性神经元中的丝氨酸/苏氨酸激酶活性的变化，该精神分裂症患者在精神分裂症1（DISC1）基因和相应的对照中呈现4 bp突变。使用kinome肽阵列，我们证明了DISC1细胞中的大规模异常，包括丝氨酸/苏氨酸激酶活性的整体降低，以及激酶活性的变化，包括AMP活化蛋白激酶（AMPK），细胞外信号调节激酶（ERK）和一千零一个氨基酸（TAO）激酶。使用将DISC1突变引入对照细胞系或在精神分裂症细胞系中恢复的等基因细胞系，我们将大多数这些变化归因于DISC1突变的存在的直接影响。研究DISC1激酶网络下游的基因表达特征，并将其映射到从基于集成网络的细胞特征库（LINCS）数据库获得的微扰蛋白特征上，我们可以提出能够逆转DISC1激酶失调基因表达的新型药物靶标签名。共，