| 1 | J. Neurosci. Res. 2007 Jun 85: 1762-73 |
|---|---|
| PMID | 17457889 |
| Title | Neuronal PAS domain protein 1 regulates tyrosine hydroxylase level in dopaminergic neurons. |
| Abstract | Catecholamines (dopamine, norepinephrine, and epinephrine) are all synthesized from a common pathway in which tyrosine hydroxylase (TH) is the rate-limiting enzyme. Dopamine is the main neurotransmitter present in dopaminergic neurons of the ventral midbrain, where dysfunction of these neurons can lead to Parkinson's disease and schizophrenia. Neuronal PAS domain protein 1 (NPAS1) was identified as one of the genes up-regulated during dopaminergic MN9D cell differentiation. We found that there was a corresponding decrease in TH level during MN9D differentiation. Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter. Expression studies also confirmed a decrease in TH level in the ventral midbrain during mouse development, concomitant with an increase in NPAS1 level. These results suggest that NPAS1 plays a novel and important role in regulating TH level of dopaminergic neurons in the ventral midbrain during development. |
| SCZ Keywords | schizophrenia |
| 2 | J Neural Transm (Vienna) 2008 -1 115: 513-9 |
| PMID | 18335162 |
| Title | Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia. |
| Abstract | Studies suggest that GAD1 gene is a functional candidate susceptibility gene for schizophrenia. In order to investigate the contribution of GAD1 gene to the etiology of schizophrenia in Chinese, we carried out a family-based association study between GAD1 gene and schizophrenia in 235 Chinese Han family trios. The GAD1 gene is comprehensively analyzed using a systematic mutation scan and the following-up association studies between common SNPs and schizophrenia in both single-locus and haplotype levels. Altogether, we have found 17 variants including 10 SNPs in 5'-flanking regions, 4 SNPs and one novel in-del in intronic regions and 2 SNPs (one novel SNP) in the 3'-untranslated region (UTR). Using the transmission disequilibrium test of the 9 common SNPs out of 17 variants, Significant evidence of SNP rs3791878-G allele in 5'-flanking region of GAD1 was preferentially transmitted to both the all offsprings of the trios (P = 0.0063, respectively; odds ratio = 1.83; 95% confidence interval: 1.26-2.65) and the male offsprings the trios (P = 0.0045, respectively; odds ratio = 2.21; 95% confidence interval: 1.37-3.56). Haplotype analysis suggested that rs3762556(C)-rs3791878(G)-rs6755102(C) is the major risky haplotype preferentially transmitted in both all the trios and male-offspring trios (Global P = 0.016 and 0.012, respectively). The gender-dependent of the risk of SNP rs3791878 suggest the complexity of GAD1 gene in schizophrenia. Given that the switch from G to T in SNP rs3791878 might cause the loss of ARNT and XBP1 transcriptional factor binding sites using a bioinformatics approach, our positive findings of this SNP support the hypothesis that the abruption of GAD1 gene is important to the risk of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 3 | Schizophr. Res. 2010 Jul 120: 143-9 |
| PMID | 20466522 |
| Title | Association of NPAS3 exonic variation with schizophrenia. |
| Abstract | We previously identified the neuronal PAS3 (NPAS3) gene as a candidate gene for schizophrenia. A mother and daughter, both with schizophrenia, were carriers of a translocation, t(9;14)(q34;q13), that disrupts the NPAS3 gene. The gene is located at 14q13, a region implicated in schizophrenia and bipolar disorder in various linkage studies. NPAS3 belongs to the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) transcription factor family, involved in diverse processes including the regulation of cell differentiation and circadian rhythms, and the development and function of the nervous system. The 12 exons encoding NPAS3 were sequenced in DNA from individuals with schizophrenia. NPAS3 variants were identified in exons 6 and 12, initially in 12 patients only. These two exons were then sequenced in 83 patients and 83 controls. Three common variants of NPAS3, also found in controls, showed a positive association with schizophrenia (NM_001164749: rs12434716, c.1654G>C, p=0.009; rs10141940, c.2208C>T, p=0.01; rs10142034, c.2262C>G, p=0.01). The c.1654G>C variant, results in an p.Ala552Pro change and may affect NPAS3 protein function directly. Alternatively, the three SNPs may affect the splicing of NPAS3 transcripts, as they are each located within putative exonic splicing enhancer (ESE) motifs (ESEFinder). A c.726C>T variant, identified in three patients, is located in an ESE element and is predicted to reduce the function of the motif. Other variants, identified in controls, included c.2089G>A (p.Gly697Ser) and c.2097T>C. Our identification of potentially defective NPAS3 variants supports recent studies that implicate perturbations in NPAS3 pathways in impaired neurogenesis and psychosis. |
| SCZ Keywords | schizophrenia |
| 4 | Neuropsychopharmacology 2010 May 35: 1315-24 |
| PMID | 20107430 |
| Title | A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. |
| Abstract | Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21+/-4.51 vs 4.33+/-3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-ARNT-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets. |
| SCZ Keywords | schizophrenia |
| 5 | Mol. Psychiatry 2012 Mar 17: 267-79 |
| PMID | 21709683 |
| Title | Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3. |
| Abstract | The basic helix-loop-helix PAS (Per, ARNT, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis--but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and ?-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients. |
| SCZ Keywords | schizophrenia |
| 6 | Nature 2013 Sep 501: 444-8 |
| PMID | 23975098 |
| Title | The structural mechanism of KCNH-channel regulation by the eag domain. |
| Abstract | The KCNH voltage-dependent potassium channels (ether-à-go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-ARNT-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4-S5 linker or the CNBHD. Here we present a 2?Å resolution crystal structure of the eag domain-CNBHD complex of the mouse EAG1 (also known as KCNH1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain primarily involves the CNBHD. Notably, the structure reveals that a number of LQT2 mutations at homologous positions in human ERG, in addition to cancer-associated mutations in EAG channels, localize to the eag domain-CNBHD interface. Furthermore, mutations at the interface produced marked effects on channel gating, demonstrating the important physiological role of the eag domain-CNBHD interaction. Our structure of the eag domain-CNBHD complex of mouse EAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels. |
| SCZ Keywords | schizophrenia |
| 7 | J. Chem. Neuroanat. 2014 Nov 61-62: 64-71 |
| PMID | 25017895 |
| Title | Differential distribution of hypoxia-inducible factor 1-beta (ARNT or ARNT2) in mouse substantia nigra and ventral tegmental area. |
| Abstract | Hypoxia has been proposed as a mechanism underlying gene-environment interactions in the neurodevelopmental model of schizophrenia, and hypoxia-inducible factor 1 (HIF-1) could mediate the interactions. In the current study, we analyzed the HIF-1 beta subunit, as formed by aryl hydrocarbon receptor nuclear translocator (ARNT) or ARNT2, in the mouse substantia nigra (SN) and the ventral tegmental area (VTA). We performed immunohistochemical studies of ARNT and ARNT2 in the adult mouse brain, and colocalization analyses, with specific emphasis on dopaminergic cells, i.e. tyrosine hydroxylase (TH) immunoreactive cells. Bioinformatic analyses identified shared protein partners for ARNT and ARNT2. ARNT immunoreactivity showed widespread neuronal labeling without overt regional specificity. We observed co-localization of ARNT and TH in the SN compacta and VTA. Nuclei strongly labeled for ARNT2 were observed in the SN reticulata, while only weak immunoreactivity for ARNT2 was found in TH-immunoreactive neurons in SN compacta and VTA. Stereological analysis showed that ARNT was preferentially expressed in dopaminergic neurons in SN compacta and VTA. Nuclei strongly labeled for ARNT2 were present in neocortex and CA1 of hippocampus. Differential expression of ARNT and ARNT2 in dopaminergic neurons may relate to the vulnerability of distinct dopaminergic projections to hypoxia and to functional vulnerability in schizophrenia and other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 8 | BMC Med. Genet. 2014 -1 15: 37 |
| PMID | 24674381 |
| Title | NPAS3 variants in schizophrenia: a neuroimaging study. |
| Abstract | This research is a one-site neuroimaging component of a two-site genetic study involving patients with schizophrenia at early and later stages of illness. Studies support a role for the neuronal Per-ARNT-Sim 3 (NPAS3) gene in processes that are essential for normal brain development. Specific NPAS3 variants have been observed at an increased frequency in schizophrenia. In humans, NPAS3 protein was detected in the hippocampus from the first trimester of gestation. In addition, NPAS3 protein levels were reduced in the dorsolateral prefrontal cortex of some patients with schizophrenia. Npas3 knockout mice display behavioural, neuroanatomical and structural changes with associated severe reductions in neural precursor cell proliferation in the hippocampal dentate gyrus. This study will evaluate the hypothesis that the severe reductions in neural precursor cell proliferation in the dentate gyrus will be present to some degree in patients carrying schizophrenia-associated NPAS3 variants and less so in other patients. Patients enrolled in the larger genetic study (n = 150) will be invited to participate in this neuroimaging arm. The genetic data will be used to ensure a sample size of 45 participants in each genetic subgroup of patients (with and without NPAS3 variants). In addition, we will recruit 60 healthy controls for acquisition of normative data. The following neuroimaging measures will be acquired from the medial temporal region: a) an index of the microcellular environment; b) a macro-structural volumetric measure of the hippocampus; and c) concentration levels of N-acetylaspartate, a marker of neuronal health. This study will help to establish the contribution of the NPAS3 gene and its variants to brain tissue abnormalities in schizophrenia. Given the genetic and phenotypic heterogeneity of the disorder and the large variation in outcomes, the identification of biological subgroups may in future support tailoring of treatment approaches in order to optimize recovery. |
| SCZ Keywords | schizophrenia |
| 9 | PLoS ONE 2014 -1 9: e85768 |
| PMID | 24465693 |
| Title | Human variants in the neuronal basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) transcription factor complex NPAS4/ARNT2 disrupt function. |
| Abstract | Neuronal Per-ARNT-Sim homology (PAS) Factor 4 (NPAS4) is a neuronal activity-dependent transcription factor which heterodimerises with ARNT2 to regulate genes involved in inhibitory synapse formation. NPAS4 functions to maintain excitatory/inhibitory balance in neurons, while mouse models have shown it to play roles in memory formation, social interaction and neurodegeneration. NPAS4 has therefore been implicated in a number of neuropsychiatric or neurodegenerative diseases which are underpinned by defects in excitatory/inhibitory balance. Here we have explored a broad set of non-synonymous human variants in NPAS4 and ARNT2 for disruption of NPAS4 function. We found two variants in NPAS4 (F147S and E257K) and two variants in ARNT2 (R46W and R107H) which significantly reduced transcriptional activity of the heterodimer on a luciferase reporter gene. Furthermore, we found that NPAS4.F147S was unable to activate expression of the NPAS4 target gene BDNF due to reduced dimerisation with ARNT2. Homology modelling predicts F147 in NPAS4 to lie at the dimer interface, where it appears to directly contribute to protein/protein interaction. We also found that reduced transcriptional activation by ARNT2 R46W was due to disruption of nuclear localisation. These results provide insight into the mechanisms of NPAS4/ARNT dimerisation and transcriptional activation and have potential implications for cognitive phenotypic variation and diseases such as autism, schizophrenia and dementia. |
| SCZ Keywords | schizophrenia |