Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia

• Authors: Eduard Bentea, Vrije Universiteit Brussel; Erica A.K. Depasquale, Cincinnati Children's Hospital Medical Center; Sinead M. O'Donovan, University of Toledo; Courtney R. Sullivan, Cyagen US; Micah Simmons, University of Alabama at Birmingham; James H. Meador-Woodruff, University of Alabama at Birmingham; Ying Zhou, Emory University; Chongchong Xu, Emory University; Bing Bai, St. Jude Children's Research Hospital; Junmin Peng, St. Jude Children's Research Hospital; Hongjun Song, University of Pennsylvania; Guo-li Ming, University of Pennsylvania; Jarek Meller, Cincinnati Children's Hospital Medical Center; Zhexing Wen, Emory University; Robert E. McCullumsmith, University of Toledo
• Journal Title: Molecular Omics
• Volume: Volume 15, Number 3
• Publisher: Royal Society of Chemistry | 2019-01-01, Pages 173-188
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1039/c8mo00173a
• Subjects: Psychology, Clinical; Biology, Neuroscience; Biology, Genetics
• Keywords: protein kinase; signal transduction; central nervous system; neurodevelopment; synaptic transmission; plasticity; neurological disorders; neuropsychiatric disorders; schizophrenia; serine/threonine kinase; induced pluripotent stem cells; 4-bp mutation; DISC1

Abstract

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.