Genetic and post-mortem mRNA analysis of the 14-3-3 genes that encode phosphoserine/threonine-binding regulatory proteins in schizophrenia and bipolar disorder

Wong, Albert H.C.; Likhodi, Olga; Trakalo, Joseph; Yusuf, Muneeb; Sinha, Anuradha; Pato, Carlos N.; Pato, Michele T.; Tol, Hubert H.M. Van; Kennedy, James L.

doi:10.1016/j.schres.2005.06.009

Cited by 43 publications

(36 citation statements)

References 39 publications

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“…They were found dysregulated also in other reports on the schizophrenia proteome [32]. The 14-3-3 protein family is highly associated with neurotransmitting processes [28], with some isoforms particularly enriched in synapses, and the YWHAZ and YWHAE genes were previously associated with schizophrenia [33][34][35]. For instance, broad 14-3-3 functional knockout mice, in addition to showing schizophrenia-like behavior, have high dopamine levels and a decrease in dendritic complexity and spine density, defects linked to schizophrenia [36].…”

Section: Resultssupporting

confidence: 57%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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Schizophrenia is an incurable and debilitating mental disorder that may affect up to 1% of the world population. Morphological, electrophysiological, and neurophysiological studies suggest that the corpus callosum (CC), which is the largest portion of white matter in the human brain and responsible for inter-hemispheric communication, is altered in schizophrenia patients. Here, we employed mass spectrometry-based proteomics to investigate the molecular underpinnings of schizophrenia. Brain tissue samples were collected postmortem from nine schizophrenia patients and seven controls at the University of Heidelberg, Germany. Because the CC has a signaling role, we collected cytoplasmic (soluble) proteins and submitted them to nano-liquid chromatography-mass spectrometry (nano LC-MS/MS). Proteomes were quantified by label-free spectral counting. We identified 5678 unique peptides that corresponded to 1636 proteins belonging to 1512 protein families. Of those proteins, 65 differed significantly in expression: 28 were upregulated and 37 downregulated. Our data increased significantly the knowledge derived from an earlier proteomic study of the CC. Among the differentially expressed proteins are those associated with cell growth and maintenance, such as neurofilaments and tubulins; cell communication and signaling, such as 14-3-3 proteins; and oligodendrocyte function, such as myelin basic protein and myelin-oligodendrocyte glycoprotein. Additionally, 30 of the differentially expressed proteins were found previously in other proteomic studies in postmortem brains; this overlap in findings validates the present study and indicates that these proteins may be markers consistently associated with schizophrenia. Our findings increase the understanding of schizophrenia pathophysiology and may serve as a foundation for further treatment strategies.

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Section: Resultssupporting

confidence: 57%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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“…Particularly, genetic and postmortem analyses have identified certain 14-3-3 isoforms as candidate risk genes for schizophrenia (Toyooka et al, 1999;Vawter et al, 2001;Wong et al, 2003Wong et al, , 2005Ikeda et al, 2008). Additionally, a reduction of synaptic 14-3-3-in the hippocampus has been observed in mice with age-related cognitive decline (VanGuilder et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

14-3-3 Proteins Are Required for Hippocampal Long-Term Potentiation and Associative Learning and Memory

et al. 2014

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14-3-3 is a family of regulatory proteins highly expressed in the brain. Previous invertebrate studies have demonstrated the importance of 14-3-3 in the regulation of synaptic functions and learning and memory. However, the in vivo role of 14-3-3 in these processes has not been determined using mammalian animal models. Here, we report the behavioral and electrophysiological characterization of a new animal model of 14-3-3 proteins. These transgenic mice, considered to be a 14-3-3 functional knock-out, express a known 14-3-3 inhibitor in various brain regions of differentfounderlines.Weidentifyafounder-specificimpairmentinhippocampal-dependentlearningandmemorytasks,aswellasacorrelated suppression in long-term synaptic plasticity of the hippocampal synapses. Moreover, hippocampal synaptic NMDA receptor levels are selectively reduced in the transgenic founder line that exhibits both behavioral and synaptic plasticity deficits. Collectively, our findings provide evidence that 14-3-3 is a positive regulator of associative learning and memory at both the behavioral and cellular level.

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“…Several previous transcriptomic and proteomic analyses have identified alterations in 14-3-3 protein isoforms in postmortem tissue of people with schizophrenia and bipolar disorder (Altar et al, 2009;English et al, 2011), and genetic association with these disorders has been reported (Grover et al, 2009;Jia et al, 2004;Wong et al, 2005). Mice lacking the isoform 14-3-3ζ display significant deficits in hippocampus-dependent functions such as working memory, sensory gating, and associative learning (Cheah et al, 2012;Qiao et al, 2014) and these changes are associated with decreased levels of NMDA receptors in the postsynaptic density (PSD) of CA1 pyramidal neurons, leading to deficits in hippocampal long-term synaptic plasticity (Qiao et al, 2014).…”

Section: -3-3 Signalingmentioning

confidence: 99%

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

Schubert¹,

Föcking²,

Cotter³

2015

Schizophrenia Research

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Genetic and post-mortem mRNA analysis of the 14-3-3 genes that encode phosphoserine/threonine-binding regulatory proteins in schizophrenia and bipolar disorder

Cited by 43 publications

References 39 publications

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

14-3-3 Proteins Are Required for Hippocampal Long-Term Potentiation and Associative Learning and Memory

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

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