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Derek J Blake - One of the best experts on this subject based on the ideXlab platform.
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TRIM32 is an E3 ubiquitin ligase for Dysbindin. HumMol Genet. 2009; 18(13):2344–58. Epub 2009/04/08. ddp167. PMID: 19349376. doi: 10.1093/hmg/ddp167
2016Co-Authors: Matthew Locke, Matthew A. Benson, Caroline L. Tinsley, Derek J BlakeAbstract:Mutations in the gene encoding tripartite motif protein 32 (TRIM32) cause two seemingly diverse diseases: limb-girdle muscular dystrophy type 2H (LGMD2H) or sarcotubular myopathy (STM) and Bardet–Biedl syndrome type 11(BBS11). Although TRIM32 is involved in protein ubiquitination, its substrates and the molecular consequences of disease-causing mutations are poorly understood. In this paper, we show that TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. Using the yeast two-hybrid system, we found that TRIM32 binds and ubiquitinates Dysbindin, a protein implicated in the genetic aetiology of schizophrenia, augmenting its degradation. Small-interfering RNA-mediated knock-down of TRIM32 in myoblasts resulted in elevated levels of Dysbindin. Importantly, the LGMD2H/ STM-associated TRIM32 mutations, D487N and R394H impair ubiquitin ligase activity towards Dysbindin and were mislocalized in heterologous cells. These mutants were able to self-associate and also co-immuno-precipitated with wild-type TRIM32 in transfected cells. Furthermore, the D487N mutant could bind to both Dysbindin and its E2 enzyme but was defective in monoubiquitination. In contrast, the BBS11 mutant P130S did not show any biochemical differences compared with the wild-type protein. Our data identify TRIM32 as a regulator of Dysbindin and demonstrate that the LGMD2H/STM mutations may impair substrate ubiquitination
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synaptic Dysbindin 1 reductions in schizophrenia occur in an isoform specific manner indicating their subsynaptic location
PLOS ONE, 2011Co-Authors: Konrad Talbot, Derek J Blake, Natalia Louneva, Julia W Cohen, Hala Kazi, Steven E ArnoldAbstract:Background: An increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes Dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific. Methodology/Principal Findings: Using Western blotting of tissue fractions, we first determined the synaptic localization of the three major Dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (Dysbindin-1B) or with postsynaptic densities (Dysbindin-1A and -1C). Using Western blotting on pSTG (n = 15) and HF (n = 15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic Dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic Dysbindin-1A reductions averaging 48% (p = 0.0007) without alterations in other Dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic Dysbindin-1A, but 67% showed synaptic reductions in Dysbindin-1B averaging 33% (p = 0.0256), while 80% showed synaptic reductions in Dysbindin-1C averaging 35% (p = 0.0171). Conclusions/Significance: Given the distinctive subsynaptic localization of Dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in Dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in Dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory.
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Dysbindin 1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform specific manner unrelated to Dysbindin 1 mrna expression
Human Molecular Genetics, 2009Co-Authors: Junxia Tang, Derek J Blake, Natalia Louneva, Julia W Cohen, Steven E Arnold, Robert P Legros, Lilly Yeh, Changgyu Hahn, Konrad TalbotAbstract:DTNBP1 (dystrobrevin binding protein 1) remains a top candidate gene in schizophrenia. Reduced expression of this gene and of its encoded protein, Dysbindin-1, have been reported in the brains of schizophrenia cases. It has not been established, however, if the protein reductions encompass all Dysbindin-1 isoforms or if they are associated with decreased DTNBP1 gene expression. Using a matched pairs design in which each of 28 Caucasian schizophrenia cases was matched in age and sex to a normal Caucasian control, Western blotting of whole-tissue lysates of dorsolateral prefrontal cortex (DLPFC) revealed significant reductions in Dysbindin-1C (but not in Dysbindin-1A or -1B) in schizophrenia (P = 0.022). These reductions occurred without any significant change in levels of the encoding transcript in the same tissue samples and in the absence of the only DTNBP1 risk haplotype for schizophrenia reported in the USA. Indeed, no significant correlations were found between case–control differences in any Dysbindin-1 isoform and the case–control differences in its encoding mRNA. Consequently, the mean 60% decrease in Dysbindin-1C observed in 71% of our case–control pairs appears to reflect abnormalities in mRNA translation and/or processes promoting Dysbindin-1C degradation (e.g. oxidative stress, phosphorylation and/or ubiquitination). Given the predominantly post-synaptic localization of Dysbindin-1C and known post-synaptic effects of Dysbindin-1 reductions in the rodent equivalent of the DLPFC, the present findings suggest that decreased Dysbindin-1C in the DLPFC may contribute to the cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction in fast-spiking interneurons.
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TRIM32 is an E3 ubiquitin ligase for Dysbindin
Human molecular genetics, 2009Co-Authors: Matthew Locke, Matthew A. Benson, Caroline L. Tinsley, Derek J BlakeAbstract:Mutations in the gene encoding tripartite motif protein 32 (TRIM32) cause two seemingly diverse diseases: limb-girdle muscular dystrophy type 2H (LGMD2H) or sarcotubular myopathy (STM) and Bardet–Biedl syndrome type 11(BBS11). Although TRIM32 is involved in protein ubiquitination, its substrates and the molecular consequences of disease-causing mutations are poorly understood. In this paper, we show that TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. Using the yeast two-hybrid system, we found that TRIM32 binds and ubiquitinates Dysbindin, a protein implicated in the genetic aetiology of schizophrenia, augmenting its degradation. Small-interfering RNA-mediated knock-down of TRIM32 in myoblasts resulted in elevated levels of Dysbindin. Importantly, the LGMD2H/STM-associated TRIM32 mutations, D487N and R394H impair ubiquitin ligase activity towards Dysbindin and were mislocalized in heterologous cells. These mutants were able to self-associate and also co-immunoprecipitated with wild-type TRIM32 in transfected cells. Furthermore, the D487N mutant could bind to both Dysbindin and its E2 enzyme but was defective in monoubiquitination. In contrast, the BBS11 mutant P130S did not show any biochemical differences compared with the wild-type protein. Our data identify TRIM32 as a regulator of Dysbindin and demonstrate that the LGMD2H/STM mutations may impair substrate ubiquitination.
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schizophrenia genetics Dysbindin under the microscope
Trends in Neurosciences, 2004Co-Authors: Matthew A. Benson, Roy V Sillitoe, Derek J BlakeAbstract:It is well established that genetic factors strongly contribute to the susceptibility of an individual to schizophrenia. Straub, Kendler and colleagues have published the first of several articles demonstrating a genetic association between schizophrenia and the gene encoding the dystrobrevin-binding protein Dysbindin. Although no mutations in the Dysbindin gene have been found, the recent identification of a specific risk haplotype in independent samples provides further evidence that Dysbindin is a possible schizophrenia susceptibility gene.
Caroline L. Tinsley - One of the best experts on this subject based on the ideXlab platform.
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TRIM32 is an E3 ubiquitin ligase for Dysbindin. HumMol Genet. 2009; 18(13):2344–58. Epub 2009/04/08. ddp167. PMID: 19349376. doi: 10.1093/hmg/ddp167
2016Co-Authors: Matthew Locke, Matthew A. Benson, Caroline L. Tinsley, Derek J BlakeAbstract:Mutations in the gene encoding tripartite motif protein 32 (TRIM32) cause two seemingly diverse diseases: limb-girdle muscular dystrophy type 2H (LGMD2H) or sarcotubular myopathy (STM) and Bardet–Biedl syndrome type 11(BBS11). Although TRIM32 is involved in protein ubiquitination, its substrates and the molecular consequences of disease-causing mutations are poorly understood. In this paper, we show that TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. Using the yeast two-hybrid system, we found that TRIM32 binds and ubiquitinates Dysbindin, a protein implicated in the genetic aetiology of schizophrenia, augmenting its degradation. Small-interfering RNA-mediated knock-down of TRIM32 in myoblasts resulted in elevated levels of Dysbindin. Importantly, the LGMD2H/ STM-associated TRIM32 mutations, D487N and R394H impair ubiquitin ligase activity towards Dysbindin and were mislocalized in heterologous cells. These mutants were able to self-associate and also co-immuno-precipitated with wild-type TRIM32 in transfected cells. Furthermore, the D487N mutant could bind to both Dysbindin and its E2 enzyme but was defective in monoubiquitination. In contrast, the BBS11 mutant P130S did not show any biochemical differences compared with the wild-type protein. Our data identify TRIM32 as a regulator of Dysbindin and demonstrate that the LGMD2H/STM mutations may impair substrate ubiquitination
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TRIM32 is an E3 ubiquitin ligase for Dysbindin
Human molecular genetics, 2009Co-Authors: Matthew Locke, Matthew A. Benson, Caroline L. Tinsley, Derek J BlakeAbstract:Mutations in the gene encoding tripartite motif protein 32 (TRIM32) cause two seemingly diverse diseases: limb-girdle muscular dystrophy type 2H (LGMD2H) or sarcotubular myopathy (STM) and Bardet–Biedl syndrome type 11(BBS11). Although TRIM32 is involved in protein ubiquitination, its substrates and the molecular consequences of disease-causing mutations are poorly understood. In this paper, we show that TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. Using the yeast two-hybrid system, we found that TRIM32 binds and ubiquitinates Dysbindin, a protein implicated in the genetic aetiology of schizophrenia, augmenting its degradation. Small-interfering RNA-mediated knock-down of TRIM32 in myoblasts resulted in elevated levels of Dysbindin. Importantly, the LGMD2H/STM-associated TRIM32 mutations, D487N and R394H impair ubiquitin ligase activity towards Dysbindin and were mislocalized in heterologous cells. These mutants were able to self-associate and also co-immunoprecipitated with wild-type TRIM32 in transfected cells. Furthermore, the D487N mutant could bind to both Dysbindin and its E2 enzyme but was defective in monoubiquitination. In contrast, the BBS11 mutant P130S did not show any biochemical differences compared with the wild-type protein. Our data identify TRIM32 as a regulator of Dysbindin and demonstrate that the LGMD2H/STM mutations may impair substrate ubiquitination.
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Dysbindin 1 is reduced in intrinsic glutamatergic terminals of the hippocampal formation in schizophrenia
Journal of Clinical Investigation, 2004Co-Authors: Konrad Talbot, Matthew A. Benson, Caroline L. Tinsley, Changgyu Hahn, Steven J Siegel, Wess L Eidem, Edward W Thompson, Rachel J Smith, John Q Trojanowski, Raquel E GurAbstract:Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding Dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic Dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on Dysbindin-1 or VGluT-1. Our findings indicate that presynaptic Dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.
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myospryn is a novel binding partner for Dysbindin in muscle
Journal of Biological Chemistry, 2004Co-Authors: Matthew A. Benson, Caroline L. Tinsley, Derek J BlakeAbstract:Dysbindin is a coiled-coil-containing protein that was initially identified in a screen for dystrobrevin-interacting proteins. Recently, Dysbindin has been shown to be involved in the biogenesis of lysosome-related organelles and is also a major schizophrenia susceptibility factor. Although Dysbindin has been implicated in a number of different cellular processes, little is known about its function. To determine the function of Dysbindin in muscle, we performed a yeast two-hybrid screen to identify potential interacting proteins. Here we show that Dysbindin binds to a novel 413-kDa protein, myospryn, which is expressed in cardiac and skeletal muscle. The transcript encoding myospryn encompasses genethonin-3, a transcript that is down-regulated in muscle from Duchenne muscular dystrophy patients and stretch-responsive protein 553, which is up-regulated in experimental muscle hypertrophy. The C terminus of myospryn contains BBC, FN3, and SPRY domains in a configuration reminiscent of the tripartite motif protein family, as well as the Dysbindin-binding site and a region mediating self-association. Dysbindin and myospryn co-immunoprecipitate from muscle extracts and are extensively co-localized. These data demonstrate for the first time that there are tissue-specific ligands for Dysbindin that may play important roles in the different disease states involving this protein.
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hermansky pudlak syndrome type 7 hps 7 results from mutant Dysbindin a member of the biogenesis of lysosome related organelles complex 1 bloc 1
Nature Genetics, 2003Co-Authors: Qing Zhang, Derek J Blake, Caroline L. Tinsley, Naoki Oiso, Edward K Novak, Rashi Gautam, Edward P Obrien, Richard A Spritz, Neal G Copeland, Nancy A JenkinsAbstract:Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no Dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding Dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that Dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that Dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.
Victor Faundez - One of the best experts on this subject based on the ideXlab platform.
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neuronal copper homeostasis susceptibility by genetic defects in Dysbindin a schizophrenia susceptibility factor
Human Molecular Genetics, 2015Co-Authors: Avanti Gokhale, Jennifer L Larimore, Stephanie A Zlatic, Alysia D Vrailasmortimer, Heather Skye Comstra, Erica Werner, Daniel F Manvich, Michael P Iuvone, David Weinshenker, Victor FaundezAbstract:Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. Although few genes and environmental factors have been linked, the intervening cellular and molecular mechanisms connecting a disorder susceptibility gene with environmental factors remain mostly unexplored. Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product Dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. Mutations in ATP7A result in Menkes disease, a disorder of copper metabolism. Dysbindin/BLOC-1 and ATP7A genetically and biochemically interact. Furthermore, disruption of this pathway causes alteration in the transcriptional profile of copper-regulatory and dependent factors in the hippocampus of Dysbindin/BLOC-1-null mice. Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency.
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mutations in the bloc 1 subunits Dysbindin and muted generate divergent and dosage dependent phenotypes
Journal of Biological Chemistry, 2014Co-Authors: Jennifer L Larimore, Ariana P Mullin, Avanti Gokhale, Stephanie A Zlatic, Konrad Talbot, Kaela S Singleton, Junxia Tang, Karine Tornieri, Victor FaundezAbstract:Post-mortem analysis has revealed reduced levels of the protein Dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of Dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding Dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5mu/mu) and Dysbindin (Bloc1s8sdy/sdy). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5mu/mu and Bloc1s8sdy/sdy mice. Unlike Bloc1s8sdy/sdy, elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders.
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quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor Dysbindin identify novel roles of the biogenesis of lysosome related organelles complex 1
The Journal of Neuroscience, 2012Co-Authors: Avanti Gokhale, Jennifer L Larimore, Erica Werner, Andres Morenodeluca, Christa Lesemartin, Vladimir Lupashin, Yoland Smith, Victor FaundezAbstract:The Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1) is a protein complex containing the schizophrenia susceptibility factor Dysbindin, which is encoded by the gene DTNBP1 . However, mechanisms engaged by Dysbindin defining schizophrenia susceptibility pathways have not been quantitatively elucidated. Here, we discovered prevalent and novel cellular roles of the BLOC-1 complex in neuronal cells by performing large-scale Stable Isotopic Labeling of Cells in Culture (SILAC) quantitative proteomics combined with genetic analyses in Dysbindin-null mice ( Mus musculus ) and the genome of schizophrenia patients. We identified 24 proteins that associate with the BLOC-1 complex, many of which were altered in content/distribution in cells or tissues deficient in BLOC-1. New findings include BLOC-1 interactions with the COG complex, a Golgi apparatus tether, and antioxidant enzymes peroxiredoxins 1–2. Importantly, loci encoding eight of the 24 proteins are affected by genomic copy number variation in schizophrenia patients. Thus, our quantitative proteomic studies expand the functional repertoire of the BLOC-1 complex and provide insight into putative molecular pathways of schizophrenia susceptibility.
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cell biology of the bloc 1 complex subunit Dysbindin a schizophrenia susceptibility gene
Molecular Neurobiology, 2011Co-Authors: Ariana P Mullin, Avanti Gokhale, Jennifer L Larimore, Victor FaundezAbstract:There is growing interest in the biology of Dysbindin and its genetic locus (DTNBP1) due to genetic variants associated with an increased risk of schizophrenia. Reduced levels of Dysbindin mRNA and protein in the hippocampal formation of schizophrenia patients further support involvement of this locus in disease risk. Here, we discuss phylogenetically conserved Dysbindin molecular interactions that define its contribution to the assembly of the biogenesis of lysosome-related organelles complex-1 (BLOC-1). We explore fundamental cellular processes where Dysbindin and the Dysbindin-containing BLOC-1 complex are implicated. We propose that cellular, tissue, and system neurological phenotypes from Dysbindin deficiencies in model genetic organisms, and likely individuals affected with schizophrenia, emerge from abnormalities in few core cellular mechanisms controlled by BLOC-1-Dysbindin-containing complex rather than from defects in Dysbindin itself.
Ryota Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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behavioral characterization of mice overexpressing human Dysbindin 1
Molecular Brain, 2014Co-Authors: Norihito Shintani, Ryota Hashimoto, Hironori Takamura, Yusuke Onaka, Tsuyoshi Nagata, Satomi Umedayano, Akihiro Mouri, Takayoshi Mamiya, Ryota HabaAbstract:Background: The Dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if Dysbindin-1 gain-of-function is beneficial or detrimental. Results: To answer this question and gain further insight into the pathophysiology and therapeutic potential of Dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-Tg mice. Conclusions: The present findings in Dys1A-Tg mice support the role of Dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of Dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of Dysbindin-1 in vivo.
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R (2011) Correlated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking Dysbindin. PLoS One 6:e18113
2013Co-Authors: Katsunori Kobayashi, Masatoshi Takeda, Satomi Umeda-yano, Hidenaga Yamamori, Ryota HashimotoAbstract:Dysbindin-1 (dystrobrevin-binding protein 1, DTNBP1) is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippocampus, including the terminal field of the mossy fibers, and this hippocampal expression of Dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of Dysbindin in hippocampal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the Dysbindin gene. Electrophysiological recordings were made in hippocampal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in cAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the cAMP cascade by forskolin induced robust synaptic potentiation in both wildtyp
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Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia
Journal of Human Genetics, 2011Co-Authors: Hidenaga Yamamori, Ryota Hashimoto, Satomi Umeda-yano, Louise Verrall, Yuka Yasuda, Motoyuki Fukumoto, Masatoshi TakedaAbstract:The Dysbindin-1 and neuregulin-1 ( NRG-1 ) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of Dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of Dysbindin-1 , NRG-1 and two other genes ( NPY1R and GNAO1 ) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of Dysbindin-1 , NRG-1 , NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the Dysbindin-1 and NRG-1 genes.
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correlated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking Dysbindin
PLOS ONE, 2011Co-Authors: Katsunori Kobayashi, Ryota Hashimoto, Masatoshi Takeda, Satomi Umedayano, Hidenaga Yamamori, Hidenori SuzukiAbstract:Dysbindin-1 (dystrobrevin-binding protein 1, DTNBP1) is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippocampus, including the terminal field of the mossy fibers, and this hippocampal expression of Dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of Dysbindin in hippocampal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the Dysbindin gene. Electrophysiological recordings were made in hippocampal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in cAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the cAMP cascade by forskolin induced robust synaptic potentiation in both wild-type and mutant mice, this forskolin-induced potentaition correlated in magnitude with the serotonin-induced potentiation only in the mutant mice, suggesting a possible change in coupling of receptor activation to downstream signaling. These results suggest that the Dysbindin deficiency could be an essential genetic factor that causes synaptic hypersensitivity to dopamine and serotonin. The altered monoaminergic modulation at the mossy fiber synapse could be a candidate pathophysiological basis for impairment of hippocampus-dependent brain functions in schizophrenia.
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reduced rate of neural differentiation in the dentate gyrus of adult Dysbindin null sandy mouse
PLOS ONE, 2011Co-Authors: Naomi Nihonmatsukikuchi, Shinsuke Matsuzaki, Ryota Hashimoto, Masaya Tohyama, Satoko Hattori, Takiko Shinozaki, Haruka Miura, Shigeru OhotaAbstract:Genetic variations in the gene encoding Dysbindin has consistently been associated with schizophrenia and bipolar disorder, although little is known about the neural functions carried out by Dysbindin. To gain some insight into this area, we took advantage of the readily available Dysbindin-null mouse sandy (sdy-/-) and studied hippocampal neurogenesis using thymidine analogue bromodeoxuridine (BrdU). No significant differences were found in the proliferation (4 hours) or survival (1, 4 and 8 weeks after the last BrdU injection) of progenitors in the subgranular regions of the dentate gyrus between sdy-/- and sdy+/+ (control) mice. However, 4 weeks after the last BrdU injection, a significant reduction was observed in the ratio of neuronal differentiation in sdy-/- when compared to that of sdy+/+ (sdy+/+ = 87.0 ± 5.3% vs. sdy-/- = 71.3 ± 8.3%, p = 0.01). These findings suggest that Dysbindin plays a role during differentiation process in the adult hippocampal neurogenesis and that its deficit may negatively affect neurogenesis-related functions such as cognition and mood.
Neal G Copeland - One of the best experts on this subject based on the ideXlab platform.
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hermansky pudlak syndrome type 7 hps 7 results from mutant Dysbindin a member of the biogenesis of lysosome related organelles complex 1 bloc 1
Nature Genetics, 2003Co-Authors: Qing Zhang, Derek J Blake, Caroline L. Tinsley, Naoki Oiso, Edward K Novak, Rashi Gautam, Edward P Obrien, Richard A Spritz, Neal G Copeland, Nancy A JenkinsAbstract:Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no Dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding Dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that Dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that Dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.
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hermansky pudlak syndrome type 7 hps 7 results from mutant Dysbindin a member of the biogenesis of lysosome related organelles complex 1 bloc 1
Nature Genetics, 2003Co-Authors: Wei Li, Derek J Blake, Caroline L. Tinsley, Qing Zhang, Naoki Oiso, Edward K Novak, Rashi Gautam, Edward P Obrien, Richard A Spritz, Neal G CopelandAbstract:Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant Dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)