| 1 | Psychiatr. Genet. 2008 Oct 18: 226-39 |
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| PMID | 18797397 |
| Title | Coregulation of genes in the mouse brain following treatment with clozapine, haloperidol, or olanzapine implicates altered potassium channel subunit expression in the mechanism of antipsychotic drug action. |
| Abstract | Antipsychotic drugs are the most effective treatment for the psychotic symptoms of schizophrenia, yet their mechanism of action remains largely unknown. Earlier studies have shown gene expression changes in rodent brains after treatment with antipsychotic drugs. We aimed to further characterize these changes using whole-genome transcript profiling to explore coregulation of genes after multiple antipsychotic drug treatment studies. This study involved transcript profile analysis after 7-day treatment of inbred C57BL/6 mice with conventional (haloperidol) or atypical (clozapine or olanzapine) antipsychotic drugs. Microarray analysis was undertaken using whole-brain mRNA on Affymetrix 430v2 arrays, with quantitative reverse transcriptase-PCR used to confirm gene expression changes. Western blotting was also used to explore translation of gene dysregulation to protein changes and to explore anatomical specificity of such changes. Thirteen genes showed verified regulation by multiple antipsychotic drugs - three genes significantly upregulated and 10 genes significantly downregulated by treatment. These genes encode proteins that function in various biological processes including neurogenesis, cell adhesion, and four genes are involved in voltage-gated ion channels: neural precursor cell developmentally downregulated gene 4 (NEDD4), Kv channel interacting protein 3 (KChip3), potassium voltage-gated channel, shaker-related subfamily, alpha1 (Kcna1) encoding Kv1.1 protein and beta1 (Kcnab1) encoding Kvbeta1 protein. The translation of these gene expression changes to protein dysregulation for Kv1.1, KCHIP3, and NEDD4 was confirmed by western blot, with regional protein analyses undertaken for Kv1.1 and KCHIP3. These results suggest that transcriptional regulation of ion channels, crucial for neurotransmission, may play a role in mediating antipsychotic drug effects. |
| SCZ Keywords | schizophrenia |
| 2 | J. Physiol. (Lond.) 2010 Sep 588: 3349-54 |
| PMID | 20530112 |
| Title | Significance of SGK1 in the regulation of neuronal function. |
| Abstract | The present brief review highlights the putative role of the serum- and glucocorticoid-inducible-kinase-1 (SGK1) in the regulation of neuronal function. SGK1 is genomically upregulated by cell shrinkage and by a variety of hormones including mineralocorticoids and glucocorticoids. The kinase is activated by insulin and growth factors via phosphatidylinositide-3-kinase (PI3-kinase), phosphoinositide-dependent kinase PDK1 and mammalian target of rapamycin mTORC2. SGK1 upregulates ion channels (e.g. SCN5A, ENaC, ASIC1, TRPV5,6, ROMK, Kv1.1-5, KCNEx/KCNQ1-5, GluR6, VSOAC, ClC2, CFTR), carriers (e.g. NHE3, NKCC2, NCC, NaPiIIb, SMIT, GLUT1,4, SGLT1, NaDC, EAAT1-5, SN1, ASCT2, 4F2/LAT, PepT2), and the Na(+)/K(+)-ATPase. SGK1 regulates enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase NEDD4-2, phosphomannose-mutase-2), and transcription factors (e.g. forkhead transcription factor Foxo3a, ?-catenin, nuclear factor-kappa-B (NFB)). SGK1 participates in the regulation of transport, hormone release, neuroexcitability, inflammation, coagulation, cell proliferation and apoptosis. SGK1 contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Presumably, SGK1 contributes to the regulation of diverse cerebral functions (e.g. memory consolidation, fear retention) and the pathophysiology of several cerebral diseases (e.g. Parkinson's disease, schizophrenia, depression, Alzheimer's disease). Despite multiple SGK1 functions, the phenotype of the SGK1 knockout mouse is mild and becomes only apparent under challenging conditions. |
| SCZ Keywords | schizophrenia |
| 3 | Neuropharmacology 2013 Nov 74: 96-107 |
| PMID | 23639431 |
| Title | Nedd4 is a specific E3 ubiquitin ligase for the NMDA receptor subunit GluN2D. |
| Abstract | NMDA receptors are a family of glutamate-gated ion channels that regulate various CNS functions such as synaptic plasticity and learning. However hypo- or hyper-activation of NMDA receptors is critically involved in many neurological and psychiatric conditions such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Thus, it is important to identify mechanisms (such as by targeted ubiquitination) that regulate the levels of individual subtypes of NMDA receptors. In this study, we used a series of tagged, carboxy terminal constructs of GluN2D to identify associating proteins from rat brain. Of seven different GluN2D C-terminal fragments used as bait, only the construct containing amino acids 983-1097 associated with an E3 ubiquitin ligase, NEDD4. A direct interaction between GluN2D and NEDD4 was confirmed both in vivo and in vitro. This association is mediated by an interaction between GluN2D's C-terminal PPXY motif and the 2nd and 3rd WW domains of NEDD4. Of the four GluN2 subunits, NEDD4 directly interacted with GluN2D and also weakly with GluN2A. NEDD4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses. These results identify NEDD4 as a novel binding partner for GluN2D and suggest a mechanism for the regulation of NMDA receptors that contain GluN2D subunits through ubiquitination-dependent downregulation. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. |
| SCZ Keywords | schizophrenia |
| 4 | Proc. Natl. Acad. Sci. U.S.A. 2013 Mar 110: 4768-73 |
| PMID | 23471985 |
| Title | Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity. |
| Abstract | Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases. |
| SCZ Keywords | schizophrenia |
| 5 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2015 Jun 32: 385-90 |
| PMID | 26037357 |
| Title | [Association of NEDD4 gene polymorphisms with schizophrenia and its clinical characteristics in Chinese Han population]. |
| Abstract | To assess the association of neural precursor cell expressed developmentally down-regulated 4 (NEDD4) with schizophrenia. Five single nucleotide polymorphisms (SNPs) of the NEDD4 gene were genotyped by TaqMan SNP genotyping assay in an independent sample of 464 individuals with schizophrenia and 487 healthy controls from eastern Han Chinese population. Clinical data were collected with a general information questionnaire and Positive and Negative Syndrome Scale (PANSS). Frequencies of rs3088077 (allelic: ?2=18.024, P=0.000; genotypic: ?2=16.634, P=0.000), rs7162435 (allelic: ?2=6.771, P=0.009; genotypic: ?2=7.352, P=0.025) and rs2303579 (allelic: ?2=11.253, P=0.001; genotypic: ?2=12.248, P=0.002) were found to be significant different between the two groups. Moreover, TT of rs7162435 was significantly correlated with scores of factors of excitement and hostility (14.53±3.925, F=3.551, P=0.029). rs3088077, rs7162435 and rs2303579 of the NEDD4 gene may be associated with schizophrenia. Moreover, the TT genotype of rs7162435 may increase the severity of excitement and hostility. Our results may provide a clue for delineating the connection between the glutamate hypothesis of schizophrenia and ubiquitination. |
| SCZ Keywords | schizophrenia |
| 6 | Biol. Psychiatry 2015 Jan 77: 158-66 |
| PMID | 25034949 |
| Title | Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets. |
| Abstract | MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs. Using high-resolution genome-wide microarrays and rigorous methods, we compared the miRNA content of rare CNVs in well-characterized cohorts of schizophrenia cases (n = 420) and comparison subjects, excluding 22q11.2 CNVs. We also performed a gene-set enrichment analysis of the predicted miRNA target genes. The schizophrenia group was enriched for the proportion of individuals with a rare CNV overlapping a miRNA (3.29-fold increase over comparison subjects, p < .0001). The presence of a rare CNV overlapping a miRNA remained a significant predictor of schizophrenia case status (p = .0072) in a multivariate logistic regression model correcting for total CNV size. In contrast, comparable analyses correcting for CNV size showed no enrichment of rare CNVs overlapping protein-coding genes. A gene-set enrichment analysis indicated that predicted target genes of recurrent CNV-overlapped miRNAs in schizophrenia may be functionally enriched for neurodevelopmental processes, including axonogenesis and neuron projection development. Predicted gene targets driving these results included CAPRIN1, NEDD4, NTRK2, PAK2, RHOA, and SYNGAP1. These data are the first to demonstrate a genome-wide role for CNVs overlapping miRNAs in the genetic risk for schizophrenia. The results provide support for an expanded multihit model of causation, with potential implications for miRNA-based therapeutics. |
| SCZ Keywords | schizophrenia |