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Convergent findings for abnormalities of the NF-?B signaling pathway in schizophrenia.

ABSTRACT: Neurons exhibit a constitutive level of nuclear factor-?B (NF-?B) signaling and this pathway plays a significant role in neurite outgrowth, activity-dependent plasticity, and cognitive function. Transcription factor analysis was performed in a microarray data set profiled in four different brain regions (n=54 comparison group; n=53 schizophrenia (SZ)). An independent postmortem cohort was used for gene expression (n=24 comparison group; n=22 SZ), protein abundance (n=8 comparison group; n=8 SZ), and NF-?B nuclear activity (n=10 comparison group; n=10 SZ) quantification. Expression quantitative trait locus analysis was performed using publicly available data. Prepulse inhibition (PPI) of the acoustic startle reflex was tested in healthy individuals (n=690). Comparison of microarray data showed that NF-?B was among the transcription factors associated with the differential expression of genes in cases vs controls. NF-?B gene and protein levels and nuclear activation were significantly decreased in the superior temporal gyrus of patients with SZ. Upstream NF-?B genes related to translocation were significantly dysregulated in SZ. The gene expression levels of an NF-?B-associated importin (KPNA4: one of the proteins responsible for the translocation of NF-?B to the nucleus) was decreased in SZ and an SNP within the KPNA4 locus was associated with susceptibility to SZ, reduced KPNA4 expression levels and attenuated PPI of the startle reflex in healthy control subjects. These findings implicate abnormalities of the NF-?B signaling pathway in SZ and provide evidence for an additional possible mechanism affecting the translocation of NF-?B signaling to the nucleus.

SUBMITTER: Roussos P

PROVIDER: S-EPMC3547205 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Convergent findings for abnormalities of the NF-κB signaling pathway in schizophrenia.

Roussos Panos P Katsel Pavel P Davis Kenneth L KL Giakoumaki Stella G SG Lencz Todd T Malhotra Anil K AK Siever Larry J LJ Bitsios Panos P Haroutunian Vahram V

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20121107 3

Neurons exhibit a constitutive level of nuclear factor-κB (NF-κB) signaling and this pathway plays a significant role in neurite outgrowth, activity-dependent plasticity, and cognitive function. Transcription factor analysis was performed in a microarray data set profiled in four different brain regions (n=54 comparison group; n=53 schizophrenia (SZ)). An independent postmortem cohort was used for gene expression (n=24 comparison group; n=22 SZ), protein abundance (n=8 comparison group; n=8 SZ), ...[more]

PMID: 23132271

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Project description:Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-α (RPTPα) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13 394 cases and 34 676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations.

Dataset Information

Convergent findings for abnormalities of the NF-?B signaling pathway in schizophrenia.

Publications

Convergent findings for abnormalities of the NF-κB signaling pathway in schizophrenia.

Similar Datasets

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