Dataset Information

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1? Neurodevelopmental Signal Transduction.

ABSTRACT: Genomic studies have repeatedly associated variants in the gene encoding the microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55?, PTEN, Akt2, GSK3?, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1?-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1? and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.

SUBMITTER: Thomas KT

PROVIDER: S-EPMC5745041 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction.

Thomas Kristen Therese KT Anderson Bart Russell BR Shah Niraj N Zimmer Stephanie Elaine SE Hawkins Daniel D Valdez Arielle Nicole AN Gu Qiaochu Q Bassell Gary Jonathan GJ

Cell reports 20170701 1

Genomic studies have repeatedly associated variants in the gene encoding the microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act down ...[more]

PMID: 28683304

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Project description: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. DISEASE MECHANISMS:A SIGNALING IMBALANCE: A study by US scientists indicates that changes in the activity of key signaling proteins may underlie core symptoms of schizophrenia. Protein kinases mediate the activation of intracellular signaling events and analyses of the kinome, the complete set of protein kinases encoded in the genome, previously revealed significant changes in phosphorylation patterns in postmortem brain tissue from patients with schizophrenia. Based on these findings, Jennifer McGuire at the University of Cincinnati and colleagues investigated the upstream regulation of these proteins. They identified both established and novel proteins associated with schizophrenia in the anterior cingulate cortex, with JNK and AKT activity being the most disrupted in schizophrenia patients. Their findings highlight how subtle changes in the activity of a small number of signaling proteins can propagate and have major consequences for mental health.

Dataset Information

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1? Neurodevelopmental Signal Transduction.

Publications

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction.

Similar Datasets

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