Article

Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Biological Psychiatry (Impact Factor: 9.47). 10/2007; 62(7):711-21. DOI: 10.1016/j.biopsych.2006.12.021
Source: PubMed

ABSTRACT Schizophrenia is characterized by complex gene expression changes. The transcriptome alterations in the prefrontal cortex have been the subject of several recent postmortem studies that yielded both convergent and divergent findings.
To increase measurement precision, we used a custom-designed DNA microarray platform with long oligonucleotides and multiple probes with replicates. The platform was designed to assess the expression of > 1800 genes specifically chosen because of their hypothesized roles in the pathophysiology of schizophrenia. The gene expression differences in dorsolateral prefrontal cortex samples from 14 matched pairs of schizophrenia and control subjects were analyzed with two technical replicates and four data mining approaches.
In addition to replicating many expression changes in synaptic, oligodendrocyte, and signal transduction genes, we uncovered and validated a robust immune/chaperone transcript upregulation in the schizophrenia samples.
We speculate that the overexpression of SERPINA3, IFITM1, IFITM2, IFITM3, CHI3L1, MT2A, CD14, HSPB1, HSPA1B, and HSPA1A in schizophrenia subjects represents a long-lasting and correlated signature of an early environmental insult during development that actively contributes to the pathophysiology of prefrontal dysfunction.

Download full-text

Full-text

Available from: Karoly Mirnics, Jul 03, 2015
0 Followers
 · 
82 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia is a heterogeneous psychiatric disorder with a broad spectrum of clinical and biological manifestations. Due to the lack of objective tests, the accurate diagnosis and selection of effective treatments for schizophrenia remains challenging. Numerous technologies have been employed in search of schizophrenia biomarkers. These studies have suggested that neuroinflammatory processes may play a role in schizophrenia pathogenesis, at least in a subgroup of patients. The evidence indicates alterations in both pro- and anti-inflammatory molecules in the central nervous system, which have also been found in peripheral tissues and may correlate with schizophrenia symptoms. In line with these findings, certain immunomodulatory interventions have shown beneficial effects on psychotic symptoms in schizophrenia patients, in particular those with distinct immune signatures. In this review, we evaluate these findings and their potential for more targeted drug interventions and the development of companion diagnostics. Although currently no validated markers exist for schizophrenia patient stratification or the prediction of treatment efficacy, we propose that utilisation of inflammatory markers for diagnostic and theranostic purposes may lead to novel therapeutic approaches and deliver more effective care for schizophrenia patients.
    Schizophrenia Research 08/2014; DOI:10.1016/j.schres.2014.07.025 · 4.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study analyzed the in vitro effects induced by sodium L-lactate on human astrocytes and the SH-SY5Y cell line, when added at concentrations of 5, 10, and 25 mmol/liter. Expression of brain-derived neurotrophic factor (BDNF), inducible nitric oxide synthase (iNOS), and heat shock protein 70 kDa (HSP70) was evaluated by Western blot analysis. Cell viability with MTT, release of nitric oxide (NO) through the Griess reaction, and production of BDNF by enzyme-linked immunoassay was determined. Data indicate that, in SH-SY5Y as well as in cortical astrocytes, after 4 hr sodium L-lactate increases the expression and release of BDNF, iNOS, and NO; after 24 hr, it turns is ineffective for the production of the neurotrophin in SH-SY5Y and not in astrocytes, but the expression of iNOS and release of NO appear to be further increased compared with those after 4 hr. Sodium L-lactate influences differently the expression of HSP70 in SH-SY5Y compared with astrocytes. We propose, based on these findings, that sodium L-lactate affects the expression of BDNF in SH-SY5Y and astrocytes in a different manner: high levels of iNOS and NO expressed in SH-SY5Y have a profound inhibitory effect on the release of BDNF related to a more limited production of HSP70 by SH-SY5Y. In conclusion, the results demonstrate differences in the responses of SH-SY5Y and astrocytes to stimulation by high levels of sodium L-lactate. Sodium L-lactate differently and dose and time dependently influences the expression and release of BDNF, iNOS, NO, and HSP70 depending on the cell type. © 2012 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 02/2013; 91(2). DOI:10.1002/jnr.23154 · 2.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral blood mononuclear cells (PBMCs) represent an accessible tissue source for gene expression profiling in schizophrenia that could provide insight into the molecular basis of the disorder. This study used the Illumina HT_12 microarray platform and quantitative real time PCR (QPCR) to perform mRNA expression profiling on 114 patients with schizophrenia or schizoaffective disorder and 80 non-psychiatric controls from the Australian Schizophrenia Research Bank (ASRB). Differential expression analysis revealed altered expression of 164 genes (59 up-regulated and 105 down-regulated) in the PBMCs from patients with schizophrenia compared to controls. Bioinformatic analysis indicated significant enrichment of differentially expressed genes known to be involved or associated with immune function and regulating the immune response. The differential expression of 6 genes, EIF2C2 (Ago 2), MEF2D, EVL, PI3, S100A12 and DEFA4 was confirmed by QPCR. Genome-wide expression analysis of PBMCs from individuals with schizophrenia was characterized by the alteration of genes with immune system function, supporting the hypothesis that the disorder has a significant immunological component in its etiology.
    Journal of Psychiatric Research 12/2012; 47(4). DOI:10.1016/j.jpsychires.2012.11.007 · 4.09 Impact Factor