A molecular pathway analysis informs the genetic background at risk for schizophrenia

Crisafulli, Concetta; Drago, Antonio; Calabrò, Marco; Spina, Edoardo; Serretti, Alessandro

doi:10.1016/j.pnpbp.2014.12.009

Cited by 23 publications

(17 citation statements)

References 74 publications

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“…Lang et al (2014) recently showed that SZ is associated with deletions of ULK4 , leading to changes in intracellular signaling through ERK and MAPK pathways. 33 They further provide evidence for disturbances in the regulation of cell migration, and neurite extension and branching due to ULK4-induced disturbances in ERK and MAPK signaling. In addition, a recent genetics-based study showed that 16 SNPs within 10 genes of the MAPK pathway (ATF1, DAXX, FOS, HRAS, JUN, MAP2K1, MAPK1, MAPK3, TRAF2 and YWHAB) were significantly associated with SZ.…”

Section: Discussionmentioning

confidence: 84%

The schizophrenia risk gene MIR137 acts as a hippocampal gene network node orchestrating the expression of genes relevant to nervous system development and function

Loohuis

Kasri²,

Glennon

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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MicroRNAs (miRs) are small regulatory molecules, which orchestrate neuronal development and plasticity through modulation of complex gene networks. microRNA-137 (miR-137) is a brain-enriched RNA with a critical role in regulating brain development and in mediating synaptic plasticity. Importantly, mutations in this miR are associated with the pathoetiology of schizophrenia (SZ), and there is a widespread assumption that disruptions in miR-137 expression lead to aberrant expression of gene regulatory networks associated with SZ. To systematically identify the mRNA targets for this miR, we performed miR-137 gain- and loss-of-function experiments in primary rat hippocampal neurons and profiled differentially expressed mRNAs through next-generation sequencing. We identified 500 genes that were bidirectionally activated or repressed in their expression by the modulation of miR-137 levels. Gene ontology analysis using two independent software resources suggested functions for these miR-137-regulated genes in neurodevelopmental processes, neuronal maturation processes and cell maintenance, all of which known to be critical for proper brain circuitry formation. Since many of the putative miR-137 targets identified here also have been previously shown to be associated with SZ, we propose that this miR acts as a critical gene network hub contributing to the pathophysiology of this neurodevelopmental disorder.

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Section: Discussionmentioning

confidence: 84%

The schizophrenia risk gene MIR137 acts as a hippocampal gene network node orchestrating the expression of genes relevant to nervous system development and function

Loohuis

Kasri²,

Glennon

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…36 conducted a thorough molecular network analysis and found that 60 single-nucleotide polymorphisms of 30 schizophrenia-associated genes are related to pathways of neurodevelopment, apoptosis, vesicle traffic, immune response, and the mitogen-activated protein kinase (MAPK) pathway, a characteristic pattern of Toll-like receptor (TLR) cascade. TLRs are implicated in the first-line detection of pathogens and danger-related signals indicating tissue damage 37–40 .…”

Section: Introductionmentioning

confidence: 99%

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Kéri

Szabó

Kelemen

2017

Sci Rep

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Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. We investigated a molecular pathway traditionally linked to the neurodevelopmental hypothesis (neuregulin 1 - ErbB), and pathogen-associated pattern recognition receptors associated with the immune hypothesis (Toll-like receptors, TLRs). We recruited 42 first-episode, drug-naïve patients with schizophrenia and 42 matched healthy control subjects. In monocytes TLR4/TLR5 and ErbB expressions were measured with flow-cytometry. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the anti-inflammatory cytokine IL-10 were determined following the stimulation of TLR4/TLR5 and ErbB. Results revealed increased TLR4/TLR5 and decreased ErbB4 expression in schizophrenia relative to the control subjects. The expression of ErbB2 and ErbB3 receptors was unaltered in schizophrenia. TLR4 stimulation resulted in lower pro-inflammatory cytokine production in schizophrenia compared to the control levels, whereas the stimulation of ErbB by neuregulin 1 led to higher pro-inflammatory cytokine levels in patients with schizophrenia relative to the control group. In healthy controls, ErbB activation was associated with a marked production of IL-10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia.

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“…Other analytes that distinguished the groups include molecules involved in neurodevelopment, glucose metabolism, lipid metabolism, sex hormones, and apoptosis. All of these pathways have been implicated to some extent in serious psychiatric disorders (Crisafulli et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Multianalyte markers of schizophrenia and bipolar disorder: A preliminary study

Dickerson

Schroeder²,

Stallings

et al. 2015

Schizophrenia Research

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A molecular pathway analysis informs the genetic background at risk for schizophrenia

Cited by 23 publications

References 74 publications

The schizophrenia risk gene MIR137 acts as a hippocampal gene network node orchestrating the expression of genes relevant to nervous system development and function

The schizophrenia risk gene MIR137 acts as a hippocampal gene network node orchestrating the expression of genes relevant to nervous system development and function

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Multianalyte markers of schizophrenia and bipolar disorder: A preliminary study

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