Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the developing field of biological psychiatry, DISC1 stands out by virtue of there being credible evidence, both genetic and biological, for a role in determining susceptibility to schizophrenia and related disorders. We highlight the methodologic paradigm that led to identification of DISC1 and review the supporting genetic and biological evidence. The original finding of DISC1 as a gene disrupted by a balanced translocation on chromosome 1q42 that segregates with schizophrenia, bipolar disorder, and recurrent major depression has sparked a number of confirmatory linkage and association studies. These indicate that DISC1 is a generalizable genetic risk factor for psychiatric illness that also influences cognition in healthy subjects. DISC1 has also been shown to interact with a number of proteins with neurobiological pedigrees, including Ndel1 (NUDEL), a key regulator of neuronal migration with endo-oligopeptidase activity, and PDE4B, a phosphodiesterase that is critical for cyclic adenosine monophosphate signaling and that is directly linked to learning, memory, and mood. Both are potential "drug" targets. DISC1 has thus emerged as a key molecular player in the etiology of major mental illness and in normal brain processes.
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PMID:The genetics and biology of DISC1--an emerging role in psychosis and cognition. 1684 95

How can we hope to explain mechanistically the schizophrenic phenotype? Perhaps through the reductionist approach of genetics, which is beginning to yield biological clues. Growing evidence supports the view that the well-established genetic risk factor DISC1 plays an important role in schizophrenia biology by interacting with FEZ1 and NDEL1 during neurodevelopment and with the phosphodiesterase PDE4B in neuronal cell signalling. Thus, DISC1 and its pathways support the neurodevelopmental hypothesis of schizophrenia and provide a mechanistic explanation for the characteristic cognitive deficits. Genetic variants of DISC1 also predispose to related affective (mood) disorders. As a consequence, we can speculate on the mechanisms of DISC1 action and possible routes to treatment for these common, debilitating brain disorders.
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PMID:Role of DISC1 in neural development and schizophrenia. 1725 2

Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, alpha-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case-control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 trio samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any.
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PMID:Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder. 1734 82

To support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse Disc1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.
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PMID:Behavioral phenotypes of Disc1 missense mutations in mice. 1748 86

The cAMP-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential selective therapeutic inhibitors. The four PDE4 genes generate several distinct protein-coding isoforms through the use of alternative promoters and 5'-coding exons. Using mouse transcripts, we identified a novel, super-short isoform of human PDE4B encoding a novel 5' terminus, which we label PDE4B5. The protein-coding region of the novel 5' exon is conserved across vertebrates, chicken, zebrafish, and fugu. Reverse-transcription-polymerase chain reaction (PCR) and quantitative (PCR) measurements show that this isoform is brain-specific. The novel protein is 58 +/- 2 kDa; it has cAMP hydrolyzing enzymatic activity and is inhibited by PDE4-selective inhibitors rolipram and cilomilast (Ariflo). Confocal and subcellular fractionation analyses show that it is distributed predominantly and unevenly within the cytosol. The 16 novel N-terminal residues of PDE4B5 are identical to the 16 N-terminal residues of the super-short isoform of PDE4D (PDE4D6), which is also brain-specific. PDE4B5 is able to bind the scaffold protein DISC1, whose gene has been linked to schizophrenia. Microarray expression profiling of the PDE4 gene family shows that specific PDE4 genes are enriched in muscle and blood fractions; however, only by monitoring the individual isoforms is the brain specificity of the super-short PDE4D and PDE4B isoforms revealed. Understanding the distinct tissue specificity of PDE4 isoforms will be important for understanding phosphodiesterase biology and opportunities for therapeutic intervention.
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PMID:PDE4B5, a novel, super-short, brain-specific cAMP phosphodiesterase-4 variant whose isoform-specifying N-terminal region is identical to that of cAMP phosphodiesterase-4D6 (PDE4D6). 1751 86

Disrupted in schizophrenia 1 (DISC1) is emerging in the eyes of many as the most promising candidate of all the schizophrenia risk genes. This viewpoint is derived from the combination of genetic, clinical, imaging and rapidly advancing cell biology data around this gene. All of these areas have been reviewed extensively recently and this review will point you towards some of these excellent papers. My own personal view of the potential importance of DISC1 was echoed in a recent review which suggested that DISC1 may be a 'Rosetta Stone' for schizophrenia research [Ross, Margolis, Reading, Pletnikov and Coyle (2006) Neuron 52, 139-153]. Our own efforts to try to understand the function of DISC1 were through identification of its protein-binding partners. Through an extensive Y2H (yeast two-hybrid) and bioinformatics effort we generated the 'DISC1-Interactome', a comprehensive network of protein-protein interactions around DISC1. In two excellent industry-academia collaborations we focused on two main interacting partners: Ndel1 (nudE nuclear distribution gene E homologue-like 1), an enigmatic protein which may have diverse functions as both a cysteine protease and a key centrosomal structural protein; and PDE4B, a cAMP-specific phosphodiesterase. I will review the work around these two protein complexes in detail.
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PMID:Dissecting DISC1 function through protein-protein interactions. 1795 30

The cyclic adenosine monophosphate-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential therapeutic inhibitors and the PDE4B gene has been associated with schizophrenia and depression. Little, however, is known of any connection between this gene family and autism, with limited effective treatment being available for autism. We measured the expression of PDE4A and PDE4B by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting in Brodmann's area 40 (BA40, parietal cortex), BA9 (superior frontal cortex), and cerebellum from subjects with autism and matched controls. We observed a lower expression of PDE4A5, PDE4B1, PDE4B3, PDE4B4, and PDE4B2 in the cerebella of subjects with autism when compared with matched controls. In BA9, we observed the opposite: a higher expression of PDE4AX, PDE4A1, and PDE4B2 in subjects with autism. No changes were observed in BA40. Our results demonstrate altered expressions of the PDE4A and PDE4B proteins in the brains of subjects with autism and might provide new therapeutic avenues for the treatment of this debilitating disorder.
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PMID:Expression of phosphodiesterase 4 is altered in the brains of subjects with autism. 1809 Mar 23

Emerging genetic and biological data strongly supports Disrupted in Schizophrenia 1 (DISC1) as a schizophrenia risk gene of great significance for not only understanding the underlying causes of schizophrenia and related disorders but potentially to open up new avenues of treatment. DISC1 appeared to be a very enigmatic protein upon the initial disclosure of its protein sequence. Though it contained some well-characterized protein domains, they did not reveal anything about possible function. Recently, the identification of its binding partners has revealed an incredible diversity of potential cellular and physiological functions. In an attempt to capture this information we set out to generate a comprehensive network of protein-protein interactions (PPIs) around DISC1. This was achieved by utilizing iterative yeast-two hybrid screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and has provided a molecular framework to explore the function of DISC1. Interrogation of the interactome has shown DISC1 to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Furthermore, potential novel therapeutic targets have also emerged as we have characterized in detail the interactions with the phosphodiesterase PDE4B in collaboration with the Porteous and Houslay labs, and with Ndel1-EOPA with Hayashi and colleagues. Many components of the interactome are themselves now being shown to be schizophrenia risk genes, or to interact with other risk genes, emphasising the power of protein interaction studies for revealing the underlying biology of a disease.
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PMID:What can we learn from the disrupted in schizophrenia 1 interactome: lessons for target identification and disease biology? 1849 5

Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.
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PMID:DISC1, PDE4B, and NDE1 at the centrosome and synapse. 1898 80

It has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles.
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PMID:Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip). 1922 52


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