Search Results (6)

Elevated risk for schizophrenia is associated with a variation in the DTNBP1 gene encoding dysbindin-1, which may underpin cognitive impairments in this prevalent neuropsychiatric disorder. The cognitive symptoms of schizophrenia involve anomalies in glutamate and dopamine signaling, particularly within the prefrontal cortex (PFC). Indeed, mice with Dtnbp1 mutations exhibit spatial and working memory deficits that are associated with deficits in glutamate release and NMDA receptor function as determined by slice electrophysiology. The present study extended the results from ex vivo approaches by examining how the Dtnbp1 mutation impacts high K+- and NMDA receptor-evoked glutamate release within the PFC using in vivo microdialysis procedures. Dntbp1 mutant mice are also reported to exhibit blunted K+-evoked dopamine release within the PFC. Thus, we examined also K+- and NMDA-evoked dopamine release within this region. Perfusion of high-concentration K+ or NMDA solutions increased the PFC levels of both dopamine and glutamate in wild-type (WT) but not in Dtnbp1 mutants (MUT), whereas mice heterozygous for the Dtnbp1 mutation (HET) exhibited blunted K+-evoked dopamine release. No net-flux microdialysis procedures confirmed elevated basal extracellular content of both glutamate and dopamine within the PFC of HET and MUT mice. These in vivo microdialysis results corroborate prior indications that Dtnbp1 mutations perturb evoked dopamine and glutamate release within the PFC, provide in vivo evidence for impaired NMDA receptor function within the PFC, and suggest that these neurochemical anomalies may be related to abnormally elevated basal neurotransmitter content. Full article

Prostate cancer (PCa) is one of the most prevalent cancers in men, yet its pathogenic pathways remain poorly understood. Transcriptomics and high-throughput sequencing can help uncover cancer diagnostic targets and understand biological circuits. Using prostate adenocarcinoma (PRAD) datasets of various web-based applications (GEPIA, UALCAN, cBioPortal, SR Plot, hTFtarget, Genome Browser, and MetaCore), we found that upregulated dysbindin domain-containing 1 (DBNDD1) expression in primary prostate tumors was strongly correlated with pathways involving the cell cycle, mitotic in KEGG, WIKI, and REACTOME database, and transcription factor-binding sites with the DBNDD1 gene in prostate samples. DBNDD1 gene expression was influenced by sample type, cancer stage, and promoter methylation levels of different cancers, such as PRAD, liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD). Regulation of glycogen synthase kinase (GSK)-3β in bipolar disorder and ATP/ITP/GTP/XTP/TTP/CTP/UTP metabolic pathways was closely correlated with the DBNDD1 gene and its co-expressed genes in PCa. DBNDD1 gene expression was positively associated with immune infiltration of B cells, Myeloid-derived suppressor cell (MDSC), M2 macrophages, andneutrophil, whereas negatively correlated with CD8⁺ T cells, T follicular helper cells, M1 macrophages, and NK cells in PCa. These findings suggest that DBNDD1 may serve as a viable prognostic marker not only for early-stage PCa but also for immunotherapies. Full article

Cognitive impairment in schizophrenia remains a clinically and pharmacologically unsolved challenge. Clinical and preclinical studies have revealed that the concomitant reduction in dysbindin (DYS) and dopamine receptor D3 functionality improves cognitive functions. However, the molecular machinery underlying this epistatic interaction has not yet been fully elucidated. The glutamate NMDA receptors and the neurotrophin BDNF, with their established role in promoting neuroplasticity, may be involved in the complex network regulated by the D3/DYS interaction. Furthermore, as inflammation is involved in the etiopathogenesis of several psychiatric diseases, including schizophrenia, the D3/DYS interaction may affect the expression levels of pro−inflammatory cytokines. Thus, by employing mutant mice bearing selective heterozygosis for D3 and/or DYS, we provide new insights into the functional interactions (single and synergic) between these schizophrenia susceptibility genes and the expression levels of key genes for neuroplasticity and neuroinflammation in three key brain areas for schizophrenia: the prefrontal cortex, striatum, and hippocampus. In the hippocampus, the epistatic interaction between D3 and DYS reversed to the wild-type level the downregulated mRNA levels of GRIN1 and GRIN2A were observed in DYS +/− and D3 +/− mice. In all the areas investigated, double mutant mice had higher BDNF levels compared to their single heterozygote counterparts, whereas D3 hypofunction resulted in higher pro−inflammatory cytokines. These results may help to clarify the genetic mechanisms and functional interactions involved in the etiology and development of schizophrenia. Full article

An emerging phenomenon in our understanding of the pathophysiology of mental illness is the idea that specific proteins may form insoluble aggregates in the brains of patients, in partial analogy to similar proteinopathies in neurodegenerative diseases. Several proteins have now been detected as forming such aggregates in the brains of patients, including DISC1, dysbindin-1 and TRIOBP-1. Recently, neuronal PAS domain protein 3 (NPAS3), a known genetic risk factor for schizophrenia, was implicated through a V304I point mutation in a family with major mental illness. Investigation of the mutation revealed that it may lead to aggregation of NPAS3. Here we investigated NPAS3 aggregation in insular cortex samples from 40 individuals, by purifying the insoluble fraction of these samples and testing them by Western blotting. Strikingly, full-length NPAS3 was found in the insoluble fraction of 70% of these samples, implying that aggregation is far more widely spread than can be accounted for by this rare mutation. We investigated the possible mechanism of aggregation further in neuroblastoma cells, finding that oxidative stress plays a larger role than the V304I mutation. Finally, we tested to see if NPAS3 aggregation could also be seen in blood serum, as a more accessible tissue than the human brain for future diagnosis. While no indication of NPAS3 aggregation was seen in the serum, soluble NPAS3 was detected, and was more prevalent in patients with schizophrenia than in those with major depressive disorder or controls. Aggregation of NPAS3 therefore appears to be a widespread and multifactorial phenomenon. Further research is now needed to determine whether it is specifically enhanced in schizophrenia or other mental illnesses. Full article

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5–7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin’s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted. Full article

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. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia. Full article