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Diego Scheggia, Rosa Mastrogiacomo, Maddalena Mereu, Sara Sannino, Richard E Straub, Marco Armando, Francesca Managò, Simone Guadagna, Fabrizio Piras, Fengyu Zhang, Joel E Kleinman, Thomas M Hyde, Sanne S Kaalund, Maria Pontillo, Genny Orso, Carlo Caltagirone, Emiliana Borrelli, Maria A De Luca, Stefano Vicari, Daniel R Weinberger, Gianfranco Spalletta, Francesco Papaleo
Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice...
June 11, 2018: Nature Communications
Glenn T Konopaske, Darrick T Balu, Kendall T Presti, Grace Chan, Francine M Benes, Joseph T Coyle
Deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia and bipolar disorder previously were shown to exhibit dendritic arbor pathology. This study sought to determine whether MARCKS, its regulatory protein dysbindin-1, and two proteins, identified using microarray data, CDC42BPA and ARHGEF6, were associated with dendritic arbor pathology in the DLPFC from schizophrenia and bipolar disorder subjects. Using western blotting, relative protein expression was assessed in the DLPFC (BA 46) grey matter from subjects with schizophrenia (n = 19), bipolar disorder (n = 17) and unaffected control subjects (n = 19)...
May 11, 2018: Schizophrenia Research
Corinna Wentzel, Igor Delvendahl, Sebastian Sydlik, Oleg Georgiev, Martin Müller
Here we explore the relationship between presynaptic homeostatic plasticity and proteasome function at the Drosophila neuromuscular junction. First, we demonstrate that the induction of homeostatic plasticity is blocked after presynaptic proteasome perturbation. Proteasome inhibition potentiates release under baseline conditions but not during homeostatic plasticity, suggesting that proteasomal degradation and homeostatic plasticity modulate a common pool of vesicles. The vesicles that are regulated by proteasome function and recruited during homeostatic plasticity are highly EGTA sensitive, implying looser Ca2+ influx-release coupling...
January 18, 2018: Nature Communications
E H Chang, K Fernando, L W E Yeung, K Barbari, T-S S Chandon, A K Malhotra
The dystrobrevin-binding protein 1 (DTNBP1) gene is a candidate risk factor for schizophrenia and has been associated with cognitive ability in both patient populations and healthy controls. DTNBP1 encodes dysbindin protein, which is localized to synaptic sites and is reduced in the prefrontal cortex and hippocampus of patients with schizophrenia, indicating a potential role in schizophrenia etiology. Most studies of dysbindin function have focused on the sandy (sdy) mice that lack dysbindin protein and have a wide range of abnormalities...
December 11, 2017: Genes, Brain, and Behavior
Cheng Fang, Xin Guo, Xing Lv, Ruozhe Yin, Xiaohui Lv, Fengsong Wang, Jun Zhao, Quan Bai, Xuebiao Yao, Yong Chen
Pancreatic ductal adenocarcinoma (PDAC) represents a biggest challenge in clinic oncology due to its invasiveness and lack of targeted therapeutics. Our recent study showed that schizophrenia susceptibility factor dysbindin exhibited significant higher level in serum of PDAC patients. However, the functional relevance of dysbindin in PDAC is still unclear. Here, we show that dysbindin promotes tumor growth both in vitro and in vivo by accelerating the G1/S phase transition in cell cycle via PI3K/AKT signaling pathway...
December 1, 2017: Journal of Molecular Cell Biology
Haitao Wang, Jiangping Xu, Philip Lazarovici, Wenhua Zheng
Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world's population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease...
September 22, 2017: International Journal of Molecular Sciences
Francisco J Estrada-Mena, Alonso Rodriguez, Patricia Mendoza-Lorenzo, Teresa Neri-Gomez, Gabriel Manjarrez-Gutierrez, Andric C Perez-Ortiz, Rosa Ordonez-Razo, Guillermo Ceballos, Francisco Villarreal, Israel Ramirez-Sanchez
INTRODUCTION: Multiple components of the dystrophin-associated protein complex (DAPC) are expressed in numerous tissues including the brain. Members of the DAPC and dysbindin are abnormally expressed in the brain of Duchenne Muscular Dystrophy (DMD) patients, which has been associated with cognitive impairments. However, little is known about the expression pattern of individual members of the DAPC in animal models of DMD and their relationship with dysbindin. METHODS: Ten mdx mice were randomly allocated into a control and intervention group [(-)-epicatechin (Epi) 1mg/kg/day for four weeks] and results compared to a wild-type mice...
September 29, 2017: Neuroscience Letters
Wei Yang, Qi Xu
Objective To explore the apoptosis in the hippocampus of dysbindin-1B(+/+) mice and the behaviors of 4-month-old dysbindin-1B(+/+) mice and wild-type mice. Methods The hippocampus of dysbindin-1B(+/+) mice and corresponding wild-type mice were assessed by TUNEL assay and transmission electron microscopy. Then twelve 4-month-old male dysbindin-1B(+/+) mice and twelve wild-type mice were enrolled. The open field and T maze test were conducted to observe locomotor activity,exploratory behaviors,and spatial memory...
June 20, 2017: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
Ankush Borlepawar, Ashraf Yusuf Rangrez, Alexander Bernt, Lynn Christen, Samuel Sossalla, Derk Frank, Norbert Frey
We have previously shown that dysbindin is a potent inducer of cardiomyocyte hypertrophy via activation of Rho-dependent serum-response factor (SRF) signaling. We have now performed a yeast two-hybrid screen using dysbindin as bait against a cardiac cDNA library to identify the cardiac dysbindin interactome. Among several putative binding proteins, we identified tripartite motif-containing protein 24 (TRIM24) and confirmed this interaction by co-immunoprecipitation and co-immunostaining. Another tripartite motif (TRIM) family protein, TRIM32, has been reported earlier as an E3 ubiquitin ligase for dysbindin in skeletal muscle...
June 16, 2017: Journal of Biological Chemistry
Nicholas J Bradshaw, Antony S K Yerabham, Rita Marreiros, Tao Zhang, Luitgard Nagel-Steger, Carsten Korth
Aggregation of specific proteins in the brains of patients with chronic mental illness as a result of disruptions in proteostasis is an emerging theme in the study of schizophrenia in particular. Proteins including DISC1 (disrupted in schizophrenia 1) and dysbindin-1B are found in insoluble forms within brain homogenates from such patients. We recently identified TRIOBP-1 (Trio-binding protein 1, also known as Tara) to be another such protein through an epitope discovery and proteomics approach by comparing post-mortem brain material from schizophrenia patients and control individuals...
June 9, 2017: Journal of Biological Chemistry
Jennifer Larimore, Stephanie A Zlatic, Miranda Arnold, Kaela S Singleton, Rebecca Cross, Hannah Rudolph, Martha V Bruegge, Andrea Sweetman, Cecilia Garza, Eli Whisnant, Victor Faundez
The neurodevelopmental factor dysbindin is required for synapse function and GABA interneuron development. Dysbindin protein levels are reduced in the hippocampus of schizophrenia patients. Mouse dysbindin genetic defects and other mouse models of neurodevelopmental disorders share defective GABAergic neurotransmission and, in several instances, a loss of parvalbumin-positive interneuron phenotypes. This suggests that mechanisms downstream of dysbindin deficiency, such as those affecting GABA interneurons, could inform pathways contributing to or ameliorating diverse neurodevelopmental disorders...
2017: Frontiers in Genetics
Xun Chen, Wenpei Ma, Shixing Zhang, Jeremy Paluch, Wanlin Guo, Dion K Dickman
Membrane trafficking pathways must be exquisitely coordinated at synaptic terminals to maintain functionality, particularly during conditions of high activity. We have generated null mutations in the Drosophila homolog of pallidin, a central subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), to determine its role in synaptic development and physiology. We find that Pallidin localizes to presynaptic microtubules and cytoskeletal structures, and that the stability of Pallidin protein is highly dependent on the BLOC-1 components Dysbindin and Blos1...
January 2017: ENeuro
Melanie M Bryan, Nathanial J Tolman, Karen L Simon, Marjan Huizing, Robert B Hufnagel, Brian P Brooks, Vladislav Speransky, James C Mullikin, William A Gahl, May Christine V Malicdan, Bernadette R Gochuico
PURPOSE: Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7. RESULTS: A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising...
April 2017: Molecular Genetics and Metabolism
Emilie I Petit, Zuzanna Michalak, Rachel Cox, Colm 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...
May 2017: 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...
February 2017: 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...
May 2017: 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
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