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)

Disrupted-in-Schizophrenia-1 (DISC-1) is a gene whose mutant truncation is associated with major psychiatric illness with a predominance of schizophrenic symptomatology. We have cloned and characterized rodent DISC-1. DISC-1 expression displays pronounced developmental regulation with the highest levels in late embryonic life when the cerebral cortex develops. In yeast two-hybrid analyses, DISC-1 interacts with a variety of cytoskeletal proteins. One of these, NudE-like (NUDEL), is associated with cortical development and is linked to LIS-1, the disease gene for a form of lissencephaly, a disorder of cortical development. The disease mutant form of DISC-1 fails to bind NUDEL. Expression of mutant, but not wild-type, DISC-1 in PC12 cells reduces neurite extension. As schizophrenia is thought to reflect defects in cortical development that are determined by cytoskeletal protein activities, the cellular disturbances we observe with mutant DISC-1 may be relevant to psychopathologic mechanisms.
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PMID:Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. 1250 98

We have previously reported a robust association between an allelic haplotype of 'Disrupted in Schizophrenia 1' (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.
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PMID:Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. 1718 86

Disrupted-in-Schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.
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PMID:DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. 1720 67

Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3epsilon. 14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. Although the functional significance of this complex in neuronal development has been reported, the transport mechanism of the complex into axons and their functions in axon formation remain essentially unknown. Here we report that Kinesin-1, a motor protein of anterograde axonal transport, was identified as a novel DISC1-interacting molecule. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3epsilon complex through DISC1, and these molecules localized mainly at cell bodies and partially in the distal part of the axons. DISC1 partially colocalized with Kinesin family member 5A, NUDEL, LIS1, and 14-3-3epsilon in the growth cones. The knockdown of DISC1 by RNA interference or the dominant-negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3epsilon at the axons and axon elongation. The knockdown or the dominant-negative form of Kinesin-1 inhibited the accumulation of DISC1 at the axons and axon elongation. Furthermore, the knockdown of NUDEL or LIS1 inhibited axon elongation. Together, these results indicate that DISC1 regulates the localization of NUDEL/LIS1/14-3-3epsilon complex into the axons as a cargo receptor for axon elongation.
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PMID:DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. 1720 68

NudE-Like (NDEL1/NUDEL), through its interaction with LIS1 and DISC1, has been implicated in the etiology of neurological disorders such as lissencephaly and schizophrenia, respectively. Subsequently, a large portion of the research done on the function of NDEL1 has been specifically targeted to its role in brain development while ignoring its function in other developing and adult tissues. To begin a more global exploration of NDEL1's function, this study characterizes the developmental expression pattern of the NDEL1 orthologs in the zebrafish embryo. Our bioinformatic analyses identified two NDEL1 orthologs in the zebrafish, ndel1a and ndel1b. ndel1a is expressed predominantly in the anterior central nervous system (CNS), trigeminal ganglia, and eyes while ndel1b is expressed in the developing somites and, later, in the CNS. In addition to the spatial differences in their expression patterns, these genes are also individually regulated in their temporal expression. Both are expressed maternally but at later time-points there are subtle differences. ndel1a expression is lost between 6 and 12 hpf but then increases to a higher, near steady state, level from 72 to 120 hpf. ndel1b expression decreases from 3 to 36 hpf and subsequently increases from 36 to 120 hpf. The non-overlapping expression patterns of these two orthologs may indicate that they have split the functional role of the one NDEL1 gene present in mammalian species. The temporal and spatial regulation of these two orthologs will aid in the characterization of the multiple functions of this gene in both the developing and mature organism.
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PMID:Expression profiles of ndel1a and ndel1b, two orthologs of the NudE-Like gene, in the zebrafish. 1748 83

DISC1 influences susceptibility to psychiatric disease and related phenotypes. Intact functions of DISC1 and its binding partners, NDEL1 and NDE1, are critical to neurodevelopmental processes aberrant in schizophrenia (SZ). Despite evidence of an NDEL1-DISC1 protein interaction, there have been no investigations of the NDEL1 gene or the relationship between NDEL1 and DISC1 in SZ. We genotyped six NDEL1 single-nucleotide polymorphisms (SNPs) in 275 Caucasian SZ patients and 200 controls and tested for association and interaction between the functional SNP Ser704Cys in DISC1 and NDEL1. We also evaluated the relationship between NDE1 and DISC1 genotype and SZ. Finally, in a series of in vitro assays, we determined the binding profiles of NDEL1 and NDE1, in relation to DISC1 Ser704Cys. We observed a single haplotype block within NDEL1; the majority of variation was captured by NDEL1 rs1391768. We observed a significant interaction between rs1391768 and DISC1 Ser704Cys, with the effect of NDEL1 on SZ evident only against the background of DISC1 Ser704 homozygosity. Secondary analyses revealed no direct relationship between NDE1 genotype and SZ; however, there was an opposite pattern of risk for NDE1 genotype when conditioned on DISC1 Ser704Cys, with NDE1 rs3784859 imparting a significant effect but only in the context of a Cys-carrying background. In addition, we report opposing binding patterns of NDEL1 and NDE1 to Ser704 versus Cys704, at the same DISC1 binding domain. These data suggest that NDEL1 significantly influences risk for SZ via an interaction with DISC1. We propose a model where NDEL1 and NDE1 compete for binding with DISC1.
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PMID:Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding. 1846 41

Schizophrenia is a complex mental disorder with a fairly high degree of heritability. Although the causes of schizophrenia remain unclear, it is now widely accepted that it is a neurodevelopmental and neurodegenerative disorder involving disconnectivity and disorder of the synapses. Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene involved in neurodevelopment, including maturation of the cerebral cortex. To identify other susceptibility genes for schizophrenia, we screened for DISC1-interacting molecules [NudE-like (NUDEL), Lissencephaly-1 (LIS1), 14-3-3epsilon (YWHAE), growth factor receptor bound protein 2 (GRB2) and Kinesin family 5A of Kinesen1 (KIF5A)], assessing a total of 25 tagging single-nucleotide polymorphisms (SNPs) in a Japanese population. We identified a YWHAE SNP (rs28365859) that showed a highly significant difference between case and control samples, with higher minor allele frequencies in controls (P(allele) = 1.01 x 10(-5) and P(genotype) = 4.08 x 10(-5) in 1429 cases and 1728 controls). Both messenger RNA transcription and protein expression of 14-3-3epsilon were also increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor alleles compared with homozygous major allele subjects. To further investigate a potential role for YWHAE in schizophrenia, we studied Ywhae(+/-) mice in which the level of 14-3-3epsilon protein is reduced to 50% of that in wild-type littermates. These mice displayed weak defects in working memory in the eight-arm radial maze and moderately enhanced anxiety-like behavior in the elevated plus-maze. Our results suggest that YWHAE is a possible susceptibility gene that functions protectively in schizophrenia.
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PMID:Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. 1865 64

Disrupted-in-schizophrenia-1 (DISC1) is one of major susceptibility factors for a wide range of mental illnesses, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions. DISC1 is located in several subcellular domains, such as the centrosome and the nucleus, and interacts with various proteins, including NudE-like (NUDEL/NDEL1) and activating transcription factor 4 (ATF4)/CREB2. Nevertheless, a role for DISC1 in vivo remains to be elucidated. Therefore, we have generated a Drosophila model for examining normal functions of DISC1 in living organisms. DISC1 transgenic flies with preferential accumulation of exogenous human DISC1 in the nucleus display disturbance in sleep homeostasis, which has been reportedly associated with CREB signaling/CRE-mediated gene transcription. Thus, in mammalian cells, we characterized nuclear DISC1, and identified a subset of nuclear DISC1 that colocalizes with the promyelocytic leukemia (PML) bodies, a nuclear compartment for gene transcription. Furthermore, we identified three functional cis-elements that regulate the nuclear localization of DISC1. We also report that DISC1 interacts with ATF4/CREB2 and a corepressor N-CoR, modulating CRE-mediated gene transcription.
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PMID:Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly. 1876 2

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

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
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PMID:Copy number variations of chromosome 16p13.1 region associated with schizophrenia. 1978 61


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