Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects

Abstract

Transcription factors play important roles in the control of neuronal function in physiological and pathological conditions. We previously reported reduced levels of transcription factor SP4 protein, but not transcript, in the cerebellum in bipolar disorder and associated with more severe negative symptoms in schizophrenia. We have recently reported phosphorylation of Sp4 at S770, which is regulated by membrane depolarization and NMDA receptor activity. The aim of this study was to investigate SP4 S770 phosphorylation in bipolar disorder and its association with negative symptoms in schizophrenia, and to explore the potential relationship between phosphorylation and protein abundance. Here we report a significant increase in SP4 phosphorylation in the cerebellum, but not the prefrontal cortex, of bipolar disorder subjects (n=10) (80% suicide) compared to matched controls (n=10). We found that SP4 phosphorylation inversely correlated with SP4 levels independently of disease status in both areas of the human brain. Moreover, SP4 phosphorylation in the cerebellum positively correlated with negative symptoms in schizophrenia subjects (n=15). Further, we observed that a phospho-mimetic mutation in truncated Sp4 was sufficient to significantly decrease Sp4 steady-state levels, while a non-phosphorylatable mutant showed increased stability in cultured rat cerebellar granule neurons. Our results indicate that SP4 S770 phosphorylation is increased in the cerebellum in bipolar disorder subjects that committed suicide and in severe schizophrenia subjects, and may be part of a degradation signal that controls Sp4 abundance in cerebellar granule neurons. This opens the possibility that modulation of SP4 phosphorylation may contribute to the molecular pathophysiology of psychotic disorders.

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder

“…However, contrasting findings have been reported as regard to the role of miR-155, with some studies suggesting it to be part of a negative feedback loop which downregulates synthesis of inflammatory cytokines [43] and other reports suggesting a putative pro-inflammatory role [42]. SP4 , one of miR-155-3p targets showing statistical significance in our study, codifies for a zinc finger transcription factor highly expressed in neurons and previously suggested to be involved in BD and SCZ [44]. Interestingly, acute in vitro treatment with lithium was found to stabilize SP4 protein via a reduction of its phosphorilation at serine 770 in cultured rat cerebellar granule neurons [45] Accordingly, the authors showed a significantly reduced phosphorilated SP4 (pSP4)/SP4 ratio in peripheral blood mononuclear cells from first-episode psychosis patients treated with lithium ( n = 6) compared to patients treated with other drugs ( n = 8) [45].…”

Identification of Hub Genes and Key Pathways Associated With Bipolar Disorder Based on Weighted Gene Co-expression Network Analysis

“…The activity of the transcription factor plays an essential role in neuronal function. Abnormal gene expression of transcription factors can affect the development and function of the nervous system and may lead to mental diseases, including BD (Pinacho et al, 2015).…”

Modeling neurodevelopmental cognitive deficits in tasks with cross‐species translational validity

“…The specificity protein‐4 (SP4), a neurodevelopmental transcription factor, has been associated with numerous psychiatric disorders with reduced expression observed in first‐episode schizophrenia patients (Fuste et al ). SP4 acts to ensure appropriate neuronal migration during development (Ramos et al ; Zhou et al ) and polymorphisms have been associated with SZ, BD and MDD (Pinacho et al , ; Zhou et al , ). Reducing Sp4 expression in mice results in several cognitive dysfunctions including diminished vigilance driven by lower hit rate in the 5C‐CPT and increased trials to acquire reward associations in a within‐session probabilistic learning task (Young et al ).…”