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Emilie I Petit, Zuzanna Michalak, Rachel Cox, C M P O'Tuathaigh, Niamh Clarke, Orna Tighe, Konrad Talbot, Derek Blake, Josephine Joel, Alexander Shaw, Steven A Sheardown, Alastair D Morrison, Stephen Wilson, Ellen M Shapland, David C Henshall, James N Kew, Brian P Kirby, John L Waddington
Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B and C) remain unknown, we generated a novel mutant mouse, dys-1A(-/-), with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment...
December 16, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Avanti Gokhale, Cortnie Hartwig, Amanda H Freeman, Ravi Das, Stephanie A Zlatic, Rachel Vistein, Amelia Burch, Guillemette Carrot, Arielle F Lewis, Sheldon Nelms, Dion K Dickman, Manojkumar A Puthenveedu, Daniel N Cox, Victor Faundez
: Proteome modifications downstream of monogenic or polygenic disorders have the potential to uncover novel molecular mechanisms participating in pathogenesis and/or extragenic modification of phenotypic expression. We tested this idea by determining the proteome sensitive to genetic defects in a locus encoding dysbindin, a protein required for synapse biology and implicated in schizophrenia risk. We applied quantitative mass spectrometry to identify proteins expressed in neuronal cells the abundance of which was altered after downregulation of the schizophrenia susceptibility factor dysbindin (Bloc1s8) or two other dysbindin-interacting polypeptides, which assemble into the octameric biogenesis of lysosome-related organelles complex 1 (BLOC-1)...
December 7, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
C Prats, B Arias, J Moya-Higueras, E Pomarol-Clotet, M Parellada, A González-Pinto, V Peralta, M I Ibáñez, M Martín, L Fañanás, M Fatjó-Vilas
BACKGROUND: The interest in studying gene-gene interactions is increasing for psychiatric diseases such as schizophrenia-spectrum disorders (SSD), where multiple genes are involved. Dysbindin-1 (DTNBP1) and Neuritin-1 (NRN1) genes have been previously associated with SSD and both are involved in synaptic plasticity. We aimed to study whether these genes show an epistatic effect on the risk for SSD. METHODS: The sample comprised 388 SSD patients and 397 healthy subjects...
November 14, 2016: European Psychiatry: the Journal of the Association of European Psychiatrists
Miranda Arnold, Rebecca Cross, Kaela S Singleton, Stephanie Zlatic, Christopher Chapleau, Ariana P Mullin, Isaiah Rolle, Carlene C Moore, Anne Theibert, Lucas Pozzo-Miller, Victor Faundez, Jennifer Larimore
AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3) and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1). Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD) and schizophrenia (SZ); yet its localization and function in neurons have not been described...
2016: Frontiers in Cellular Neuroscience
K Furukubo-Tokunaga, K Kurita, K Honjo, H Pandey, T Ando, K Takayama, Y Arai, H Mochizuki, M Ando, A Kamiya, A Sawa
No abstract text is available yet for this article.
September 2016: Molecular Psychiatry
D Becker-Krail, A Q Farrand, H A Boger, A Lavin
Notwithstanding recent advances, cognitive impairments are among the most difficult-to-treat symptoms in neuropsychiatric disorders. Deficits in information processing contributing to memory and sociability impairments are found across neuropsychiatric-related disorders. Previously, we have shown that mutations in the DTNBP1 gene (encoding dystrobrevin-binding protein 1 [dysbindin-1]) lead to abnormalities in synaptic glutamate release in the prefrontal cortex (PFC) and hippocampus and to cognitive deficits; glutamatergic transmission is important for cortical recurrent excitation that allows information processing in the PFC...
July 20, 2016: Journal of Neuroscience Research
Wei Yang, Chunyan Zhu, Yan Shen, Qi Xu
DTNBP1, which encodes dysbindin-1, is associated with cognitive impairment. Genetic evidence indicates that the C allele of rs117610176 leads to an increase in DTNBP-1b mRNA splicing in patients with paranoid schizophrenia. In addition, dysbindin-1B, rather than dysbindin-1A/C, exhibits a tendency toward toxic aggregation. In postmortem brains, dysbindin-1B not only aggregates with itself, it also co-aggregates with proteins that interact with it. However, the pathogenic mechanism underlying dysbindin-1B toxic aggregation remains unknown...
October 1, 2016: Neuroscience
Jun Ren, Tian Zhao, Yiliang Xu, Haihong Ye
Disrupted-in-schizophrenia 1 (DISC1), a gene susceptible for major mental illnesses, including schizophrenia, plays multiple roles in neural development, including neuronal proliferation, maturation, migration and neurite outgrowth. DISC1 regulates neurite length via interaction with several intracellular proteins, such as NDEL1, FEZ1 and dysbindin. However, the signal transduction mechanism upstream of DISC1 in regulating neurite outgrowth remains to be elucidated. Here we show that DISC1 interacts with the intracellular domain of close homolog of L1 (CHL1), a member of the L1 family of neural cell adhesion molecules...
October 1, 2016: Brain Research
Xin Guo, Xiaohui Lv, Cheng Fang, Xing Lv, Fengsong Wang, Dongmei Wang, Jun Zhao, Yueyun Ma, Yu Xue, Quan Bai, Xuebiao Yao, Yong Chen
Pancreatic adenocarcinoma (PDAC) is known to have a poor prognosis partly because of lack of effective biomarkers. In the test set, we investigated dysbindin (DTNBP1) as a potential biomarker for PDAC by comparing preoperative and postoperative serum mass spectrometry (MS) proteomic profilings. Of the included 50 PDAC patients, 42 (positivity of 84.0%) detected a lower MS peak in postoperative serums than preoperative ones which was then identified as dysbindin. In the verification set, receiver operating characteristics (ROC) were used to assess diagnostic efficiency...
October 15, 2016: International Journal of Cancer. Journal International du Cancer
Hiroshi Sakane, Tomohiko Makiyama, Satoru Nogami, Yukimi Horii, Kenji Akasaki, Hiromichi Shirataki
Myogenesis is required for the development of skeletal muscle. Accumulating evidence indicates that the expression of several genes are upregulated during myogenesis and these genes play pivotal roles in myogenesis. However, the molecular mechanism underlying myogenesis is not fully understood. In this study, we found that β-taxilin, which is specifically expressed in the skeletal muscle and heart tissues, was progressively expressed during differentiation of C2C12 myoblasts into myotubes, prompting us to investigate the role of β-taxilin in myogenesis...
July 15, 2016: Experimental Cell Research
Duncan Sinclair, Joseph Cesare, Mary McMullen, Greg C Carlson, Chang-Gyu Hahn, Karin E Borgmann-Winter
BACKGROUND: Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors)...
2016: Journal of Neurodevelopmental Disorders
Hidenori Ito, Rika Morishita, Koh-Ichi Nagata
Dysbindin-1 (dystrobrevin binding protein-1, DTNBP1) is now widely accepted as a potential schizophrenia susceptibility gene and accumulating evidence indicates its functions in the neural development. In this study, we tried to identify new binding partners for dysbindin-1 to clarify the novel function of this molecule. When consulted with BioGRID protein interaction database, cyclin D3 was found to be a possible binding partner for dysbindin-1. We then examined the interaction between various dysbindin-1 isoforms (dysbindin-1A, -1B and -1C) and all three D-type cyclins (cyclin D1, D2, and D3) by immunoprecipitation with the COS7 cell expression system, and found that dysbindin-1A preferentially interacts with cyclin D1...
August 2016: Biochimica et Biophysica Acta
K Furukubo-Tokunaga, K Kurita, K Honjo, H Pandey, T Ando, K Takayama, Y Arai, H Mochizuki, M Ando, A Kamiya, A Sawa
Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory...
September 2016: Molecular Psychiatry
Yong Chen, Sookhee Bang, Mary F McMullen, Hala Kazi, Konrad Talbot, Mei-Xuan Ho, Greg Carlson, Steven E Arnold, Wei-Yi Ong, Sangwon F Kim
Schizophrenia is a chronic deliberating neuropsychiatric disorder that affects about 1 % of the population. Dystrobrevin-binding protein 1 (DTNBP1 or dysbindin) is one of the Research Domain Constructs (RDoC) associated with cognition and is significantly reduced in the brain of schizophrenia patients. To further understand the molecular underpinnings of pathogenesis of schizophrenia, we have performed microarray analyses of the hippocampi from dysbindin knockout mice, and found that genes involved in the lipogenic pathway are suppressed...
February 12, 2016: Molecular Neurobiology
Nathalie Schmieg, Cristina Rocchi, Stefania Romeo, Roberto Maggio, Mark J Millan, Clotilde Mannoury la Cour
Dystrobrevin binding protein-1 (dysbindin-1), a candidate gene for schizophrenia, modulates cognition, synaptic plasticity and frontocortical circuitry and interacts with glutamatergic and dopaminergic transmission. Loss of dysbindin-1 modifies cellular trafficking of dopamine (DA) D2 receptors to increase cell surface expression, but its influence upon signaling has never been characterized. Further, the effects of dysbindin-1 upon closely related D3 receptors remain unexplored. Hence, we examined the impact of dysbindin-1 (isoform A) co-expression on the localization and coupling of human D2L and D3 receptors stably expressed in Chinese hamster ovary or SH-SY5Y cells lacking endogenous dysbindin-1...
March 2016: Journal of Neurochemistry
Qiang Yuan, Feng Yang, Yixin Xiao, Shawn Tan, Nilofer Husain, Ming Ren, Zhonghua Hu, Keri Martinowich, Julia S Ng, Paul J Kim, Weiping Han, Koh-Ichi Nagata, Daniel R Weinberger, H Shawn Je
BACKGROUND: Genetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs...
August 15, 2016: Biological Psychiatry
S Spiegel, A Chiu, A S James, J D Jentsch, K H Karlsgodt
Numerous studies have implicated DTNBP1, the gene encoding dystrobrevin-binding protein or dysbindin, as a candidate risk gene for schizophrenia, though this relationship remains somewhat controversial. Variation in dysbindin, and its location on chromosome 6p, has been associated with cognitive processes, including those relying on a complex system of glutamatergic and dopaminergic interactions. Dysbindin is one of the seven protein subunits that comprise the biogenesis of lysosome-related organelles complex 1 (BLOC-1)...
November 2015: Genes, Brain, and Behavior
Hamid M Abdolmaleky, Sara Pajouhanfar, Masoomeh Faghankhani, Mohammad Taghi Joghataei, Ashraf Mostafavi, Sam Thiagalingam
Due to the lack of genetic association between individual genes and schizophrenia (SCZ) pathogenesis, the current consensus is to consider both genetic and epigenetic alterations. Here, we report the examination of DNA methylation status of DTNBP1 promoter region, one of the most credible candidate genes affected in SCZ, assayed in saliva and post-mortem brain samples. The Illumina DNA methylation profiling and bisulfite sequencing of representative samples were used to identify methylation status of the DTNBP1 promoter region...
December 2015: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Avanti Gokhale, Alysia Vrailas-Mortimer, Jennifer Larimore, Heather S Comstra, Stephanie A Zlatic, Erica Werner, Daniel F Manvich, P Michael Iuvone, David Weinshenker, Victor Faundez
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...
October 1, 2015: Human Molecular Genetics
Cheng Fu, Dong Chen, Ruijie Chen, Qingsong Hu, Guanghui Wang
Dystrobrevin-binding protein 1 (DTNBP1), a gene encoding dysbindin-1, has been identified as a susceptibility gene for schizophrenia. Functioning with partners in synapses or the cytoplasm, this gene regulates neurite outgrowth and neurotransmitter release. Loss of dysbindin-1 affects schizophrenia pathology. Dysbindin-1 is also found in the nucleus, however, the characteristics of dysbindin in the nucleus are not fully understood. Here, we found that dysbindin-1A is degraded in the nucleus via the ubiquitin-proteasome system and that amino acids 2-41 at the N-terminus are required for this process...
2015: PloS One
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