Abnormalities of signal transduction networks in chronic schizophrenia

Sinead M. O’Donnovan,James H. Meador-Woodruff,Kathryn Hasselfeld,Jarek Meller,Shruti Marwaha,Vahram Hartounian,Adam J. Funk,Jennifer L. McGuire,John H. Hammond,Erica A. Depasquale,Robert E. McCullumsmith

doi:10.1038/s41537-017-0032-6

Abstract

Schizophrenia is a serious neuropsychiatric disorder characterized by disruptions of brain cell metabolism, microstructure, and neurotransmission. All of these processes require coordination of multiple kinase-mediated signaling events. We hypothesize that imbalances in kinase activity propagate through an interconnected network of intracellular signaling with potential to simultaneously contribute to many or all of the observed deficits in schizophrenia. We established a workflow distinguishing schizophrenia-altered kinases in anterior cingulate cortex using a previously published kinome array data set. We compared schizophrenia-altered kinases to haloperidol-altered kinases, and identified systems, functions, and regulators predicted using pathway analyses. We used kinase inhibitors with the kinome array to test hypotheses about imbalance in signaling and conducted preliminary studies of kinase proteins, phosphoproteins, and activity for kinases of interest. We investigated schizophrenia-associated single nucleotide polymorphisms in one of these kinases, AKT, for genotype-dependent changes in AKT protein or activity. Kinome analyses identified new kinases as well as some previously implicated in schizophrenia. These results were not explained by chronic antipsychotic treatment. Kinases identified in our analyses aligned with cytoskeletal arrangement and molecular trafficking. Of the kinases we investigated further, AKT and (unexpectedly) JNK, showed the most dysregulation in the anterior cingulate cortex of schizophrenia subjects. Changes in kinase activity did not correspond to protein or phosphoprotein levels. We also show that AKT single nucleotide polymorphism rs1130214, previously associated with schizophrenia, influenced enzyme activity but not protein or phosphoprotein levels. Our data indicate subtle changes in kinase activity and regulation across an interlinked kinase network, suggesting signaling imbalances underlie the core symptoms of schizophrenia.

Highlights

Schizophrenia is a serious cognitive disorder of unknown etiology.Gene expression, cytoskeletal organization, neurotransmitter systems, and more, are implicated in schizophrenia pathophysiology.[1, 2] These processes are governed to varying extents by kinase-mediated signaling events
We reported altered serine–threonine kinase activity in schizophrenia using a kinome array chip adapted for use with postmortem brain.[4]
From this analysis of all 19 substrates, we identified 7 overrepresented kinases: p21-associated kinases (PAK), G-protein-associated kinases (GRK), protein kinase A (PKA), casein kinase (CK), protein kinase D (PKD), dystrophia myotonica protein kinases (DMPK) and never in mitosis gene A-related kinases (NEK) from the original set of 19 peptides altered in schizophrenia (Supplementary Table S3)

Summary

INTRODUCTION

Cytoskeletal organization, neurotransmitter systems, and more, are implicated in schizophrenia pathophysiology.[1, 2] These processes are governed to varying extents by kinase-mediated signaling events. We postulate that schizophrenia may be a disorder mediated by subtle changes in signaling networks affecting multiple domains, including cell metabolism, molecular trafficking, inter-cellular signaling, and the functional integrity of neurocircuits. We reported altered serine–threonine kinase activity in schizophrenia using a kinome array chip adapted for use with postmortem brain.[4] Using this data set, we developed a novel bioinformatics protocol identifying kinases involved in the pathophysiology of schizophrenia. We performed additional array experiments testing the extent to which chronic antipsychotic medication alters kinase activity in brain homogenate from haloperidol decanoate-treated rats. We demonstrated that the schizophrenia-linked single nucleotide polymorphism (SNP) of protein kinase B (AKT), rs1130214, may affect AKT enzyme activity

RESULTS

Schizophrenia kinome network regulation

DISCUSSION