Neuronal alterations in AKT isotype expression in schizophrenia.

Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDPK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of conical insulin signaling pathways. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.

Altered purinergic receptor expression in the frontal cortex in schizophrenia.

ATP functions as a neurotransmitter, acting on the ubiquitously expressed family of purinergic P2 receptors. In schizophrenia (SCZ), the pathways that modulate extracellular ATP and its catabolism to adenosine are dysregulated. However, the effects of altered ATP availability on P2 receptor expression in the brain in SCZ have not been assessed. We assayed P2 receptor mRNA and protein expression in the DLPFC and ACC in subjects diagnosed with SCZ and matched, non-psychiatrically ill controls (n = 20-22/group). P2RX7, P2RX4 and male P2RX5 mRNA expression were significantly increased (p < 0.05) in the DLPFC in SCZ. Expression of P2RX7 protein isoform was also significantly increased (p < 0.05) in the DLPFC in SCZ. Significant increases in P2RX4 and male P2RX5 mRNA expression may be associated with antipsychotic medication effects. We found that P2RX4 and P2RX7 mRNA are significantly correlated with the inflammatory marker SERPINA3, and may suggest an association between upregulated P2XR and neuroinflammation in SCZ. These findings lend support for brain-region dependent dysregulation of the purinergic system in SCZ.

A bioinformatic inquiry of the EAAT2 interactome in postmortem and neuropsychiatric datasets.

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.

Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach.

The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. Identification of effective therapeutics is a crucial tool to treat those infected with SARS-CoV-2 and limit the spread of this novel disease globally. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an "omics" repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and publicly available SARS-CoV-2 infected cell lines to identify novel therapeutics. We identified a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID-19, the remaining 12 have antiviral properties and 6 have antiviral efficacy against coronaviruses specifically, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug findings are discordant with (i.e., reverse) SARS-CoV-2 transcriptome signatures generated in vitro, and a subset are also identified in transcriptome signatures generated from COVID-19 patient samples, like the MEK inhibitor selumetinib. Overall, our findings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising novel targets that are worthy of further investigation.

KEOPS complex expression in the frontal cortex in major depression and schizophrenia.

OBJECTIVES: Recently, the presence of a complete five subunit Kinase, Endopeptidase and Other Proteins of small Size (KEOPS) complex was confirmed in humans. The highly conserved KEOPS protein complex has established roles in tRNA modification, protein translation and telomere homeostasis in yeast, but little is known about KEOPS mRNA expression and function in human brain and disease. Here, we characterise KEOPS expression in post-mortem tissue from subjects diagnosed with major depression (MDD) and schizophrenia and assess whether KEOPS is associated with telomere length dysregulation in neuropsychiatric disorders. METHODS: We assessed mRNA expression of KEOPS complex subunits TP53RK, TPRKB, GON7, LAGE3, OSGEP, and OSGEP mitochondrial ortholog OSGEPL1 in the dorsolateral prefrontal cortex (DLPFC) of subjects with MDD, schizophrenia and matched non-psychiatrically ill controls (n = 20 per group) using qPCR. We conducted bioinformatic analysis using Kaleidoscope, data mining post-mortem transcriptomic datasets to characterise KEOPS expression in human brain. Finally, we assayed relative telomere length in the DLPFC using a qPCR-based assay and carried out correlation analysis with KEOPS subunit mRNA expression to determine if the KEOPS complex is associated with telomere length dysregulation in neuropsychiatric disorders. RESULTS: There were no significant changes in KEOPS mRNA expression in the DLPFC in MDD or schizophrenia compared to non-psychiatrically ill controls. Relative telomere length was not significantly altered in MDD or schizophrenia, nor was there an association between relative telomere length and KEOPS subunit gene expression in these subjects. CONCLUSIONS: This study is the first to describe KEOPS complex expression in post-mortem brain and neuropsychiatric disorders. KEOPS subunit mRNA expression is not significantly altered in the DLPFC in MDD or schizophrenia. Unlike in yeast, the KEOPS complex does not appear to play a role in telomere length regulation in humans or in neuropsychiatric disorders.

Identification of new drug treatments to combat COVID19: A signature-based approach using iLINCS.

The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. As no vaccine or drugs are currently approved to specifically treat COVID-19, identification of effective therapeutics is crucial to treat the afflicted and limit disease spread. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an "omics" repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and signatures of coronavirus-infected cell lines to identify therapeutics with concordant signatures and discordant signatures, respectively. Our findings include three FDA approved drugs that have established antiviral activity, including protein kinase inhibitors, providing a promising new category of candidates for COVID-19 interventions.