| 1 | Harefuah 2004 Jun 143: 414-6, 462 |
|---|---|
| PMID | 15524097 |
| Title | [On the relevance of protein kinase C to lithium therapy in bipolar disorder]. |
| Abstract | The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with bipolar disorder and after 5 decades this drug continues to be the mainstay of treatment of this disorder. Valproate, which is dissimilar structurally to lithium, shares most of the effects of lithium at the level of protein kinase C (PKC). Both drugs reduce the activity of PKC, though via different mechanisms. In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity is significantly elevated in manic patients, suggesting that changes of PKC activity may be a central pathological trait of the illness. The precise physiological role of PKC activity in the regulation of mood is unclear. The enzyme modulates cellular responses via phosphorylation of numerous substrate proteins. Such substrates of PKC include cytoskeletal proteins, neurotransmitter and hormone receptors, G proteins, GAP-43, MARCKS etc. Further studies are required to clarify any causal role of CPK changes in bipolar-disorder. |
| SCZ Keywords | schizophrenia |
| 2 | Neurobiol. Dis. 2010 Dec 40: 608-21 |
| PMID | 20699120 |
| Title | Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder? |
| Abstract | Glutamatergic dysfunction is strongly implicated in schizophrenia and mood disorders. GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithium or a GSK-3? inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithium, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder. |
| SCZ Keywords | schizophrenia |
| 3 | PLoS ONE 2010 -1 5: e8773 |
| PMID | 20098743 |
| Title | Dysbindin regulates the transcriptional level of myristoylated alanine-rich protein kinase C substrate via the interaction with NF-YB in mice brain. |
| Abstract | An accumulating body of evidence suggests that Dtnbp1 (Dysbindin) is a key susceptibility gene for schizophrenia. Using the yeast-two-hybrid screening system, we examined the candidate proteins interacting with Dysbindin and revealed one of these candidates to be the transcription factor NF-YB. We employed an immunoprecipitation (IP) assay to demonstrate the Dysbindin-NF-YB interaction. DNA chips were used to screen for altered expression of genes in cells in which Dysbindin or NF-YB was down regulated, while Chromatin IP and Reporter assays were used to confirm the involvement of these genes in transcription of Myristoylated alanine-rich protein kinase C substrate (MARCKS). The sdy mutant mice with a deletion in Dysbindin, which exhibit behavioral abnormalities, and wild-type DBA2J mice were used to investigate MARCKS expression. We revealed an interaction between Dysbindin and NF-YB. DNA chips showed that MARCKS expression was increased in both Dysbindin knockdown cells and NF-YB knockdown cells, and Chromatin IP revealed interaction of these proteins at the MARCKS promoter region. Reporter assay results suggested functional involvement of the interaction between Dysbindin and NF-YB in MARCKS transcription levels, via the CCAAT motif which is a NF-YB binding sequence. MARCKS expression was increased in sdy mutant mice when compared to wild-type mice. These findings suggest that abnormal expression of MARCKS via dysfunction of Dysbindin might cause impairment of neural transmission and abnormal synaptogenesis. Our results should provide new insights into the mechanisms of neuronal development and the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 4 | Mol. Psychiatry 2013 Dec 18: 1249-64 |
| PMID | 23958961 |
| Title | Discovery and validation of blood biomarkers for suicidality. |
| Abstract | Suicides are a leading cause of death in psychiatric patients, and in society at large. Developing more quantitative and objective ways (biomarkers) for predicting and tracking suicidal states would have immediate practical applications and positive societal implications. We undertook such an endeavor. First, building on our previous blood biomarker work in mood disorders and psychosis, we decided to identify blood gene expression biomarkers for suicidality, looking at differential expression of genes in the blood of subjects with a major mood disorder (bipolar disorder), a high-risk population prone to suicidality. We compared no suicidal ideation (SI) states and high SI states using a powerful intrasubject design, as well as an intersubject case-case design, to generate a list of differentially expressed genes. Second, we used a comprehensive Convergent Functional Genomics (CFG) approach to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality. CFG integrates multiple independent lines of evidence-genetic and functional genomic data-as a Bayesian strategy for identifying and prioritizing findings, reducing the false-positives and false-negatives inherent in each individual approach. Third, we examined whether expression levels of the blood biomarkers identified by us in the live bipolar subject cohort are actually altered in the blood in an age-matched cohort of suicide completers collected from the coroner's office, and report that 13 out of the 41 top CFG scoring biomarkers (32%) show step-wise significant change from no SI to high SI states, and then to the suicide completers group. Six out of them (15%) remained significant after strict Bonferroni correction for multiple comparisons. Fourth, we show that the blood levels of SAT1 (spermidine/spermine N1-acetyltransferase 1), the top biomarker identified by us, at the time of testing for this study, differentiated future as well as past hospitalizations with suicidality, in a live cohort of bipolar disorder subjects, and exhibited a similar but weaker pattern in a live cohort of psychosis (schizophrenia/schizoaffective disorder) subjects. Three other (phosphatase and tensin homolog (PTEN), myristoylated alanine-rich protein kinase C substrate (MARCKS), and mitogen-activated protein kinase kinase kinase 3 (MAP3K3)) of the six biomarkers that survived Bonferroni correction showed similar but weaker effects. Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well. Fifth, we show how a multi-dimensional approach using SAT1 blood expression levels and two simple visual-analog scales for anxiety and mood enhances predictions of future hospitalizations for suicidality in the bipolar cohort (receiver-operating characteristic curve with area under the curve of 0.813). Of note, this simple approach does not directly ask about SI, which some individuals may deny or choose not to share with clinicians. Lastly, we conducted bioinformatic analyses to identify biological pathways, mechanisms and medication targets. Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis. |
| SCZ Keywords | schizophrenia |
| 5 | Schizophr. Res. 2014 Apr 154: 36-41 |
| PMID | 24568864 |
| Title | Alterations of the myristoylated, alanine-rich C kinase substrate (MARCKS) in prefrontal cortex in schizophrenia. |
| Abstract | Abnormal synaptic plasticity has been implicated in the cognitive deficits seen in schizophrenia, where alterations have been found in neurotransmission, signaling and dendritic dynamics. Rapid rearrangement of the actin cytoskeleton is critical for plasticity and abnormalities of molecular regulators of this process are candidates for understanding mechanisms underlying these changes in schizophrenia. The myristoylated, alanine-rich C-kinase substrate (MARCKS) is crucial for many roles associated with synaptic plasticity, including facilitation of neurotransmission, dendritic branching and in turn cognitive function. Accordingly, we hypothesized that this protein is abnormally expressed or regulated in schizophrenia. We measured protein expression of MARCKS by Western blot analysis in postmortem samples of dorsolateral prefrontal cortex (DLPFC) from elderly schizophrenia patients (N=16) and a comparison group (N=20). We also assayed phosphorylated-MARCKS (pMARCKS), given the role of phosphorylation in reversing membrane association by MARCKS. We found decreased expression of both MARCKS and pMARCKS in schizophrenia. Altered myristoylation may be a mechanism that explains this down-regulation of MARCKS, so we also assayed expression of the two isoforms of the key myristoylation enzyme, NMT, and an enzymatic inhibitor of this enzyme, NMT-inhibitor protein (NIP71) by Western blotting in these same subjects. Expression did not change between groups for these proteins, suggesting a mechanism other than myristoylation is responsible for decreased MARCKS expression in schizophrenia. These data suggest a potential mechanism underlying aspects of altered synaptic plasticity observed in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 6 | Schizophr. Res. 2015 May 164: 100-8 |
| PMID | 25757715 |
| Title | Altered prefrontal cortical MARCKS and PPP1R9A mRNA expression in schizophrenia and bipolar disorder. |
| Abstract | We previously observed dendritic spine loss in the dorsolateral prefrontal cortex (DLPFC) from schizophrenia and bipolar disorder subjects. In the current study, we sought to determine if the mRNA expression of genes known to regulate the actin cytoskeleton and spines correlated with spine loss. Five candidate genes were identified using previously obtained microarray data from the DLPFC from schizophrenia and control subjects. The relative mRNA expression of the genes linked to dendritic spine growth and function, i.e. IGF1R, MARCKS, PPP1R9A, PTPRF, and ARHGEF2, was assessed using quantitative real-time PCR (qRT-PCR) in the DLPFC from a second cohort including schizophrenia, bipolar disorder, and control subjects. Functional pathway analysis was conducted to determine which actin cytoskeleton-regulatory pathways the genes of interest interact with. MARCKS mRNA expression was increased in both schizophrenia and bipolar disorder subjects. PPP1R9A mRNA expression was increased in bipolar disorder subjects. For IGF1R, mRNA expression did not differ significantly among groups; however, it did show a significant, negative correlation with dendrite length. MARCKS and PPP1R9A mRNA expression did not correlate with spine loss, but they interact with NMDA receptor signaling pathways that regulate the actin cytoskeleton and spines. MARCKS and PPP1R9A might contribute to spine loss in schizophrenia and bipolar disorder through their interactions, possibly indirect ones, with NMDA signaling pathways that regulate spine structure and function. |
| SCZ Keywords | schizophrenia |