Loss of dysbindin-1 in excitatory neurons in mice impacts NMDAR-dependent behaviors, neuronal morphology and synaptic transmission in the ventral hippocampus.

Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies.

The Role of Dopamine D3 Receptors, Dysbindin, and Their Functional Interaction in the Expression of Key Genes for Neuroplasticity and Neuroinflammation in the Mouse Brain.

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.

Hermansky-Pudlak syndrome with early onset inflammatory bowel disease due to loss of dysbindin expression.

Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of autosomal recessive genetic disorders characterized by oculocutaneous albinism, bleeding diathesis, and variable presentation of immune deficiency and dysregulation. The pathogenesis of HPS involves mutations in genes responsible for biogenesis and trafficking of lysosome-related organelles, essential for the function of melanosomes, platelet granules, and immune cell granules. Eleven genes coding for proteins in the BLOC-1, BLOC-2, BLOC-3 and AP-3 complexes have been implicated in the pathogenesis of HPS. To date, the rare subtype HPS-7 associated with bi-allelic mutations in DTNBP1 (dysbindin) has only been reported in 9 patients. We report a novel DTNBP1 splicing mutation in a 15-month-old patient with HPS-7 phenotype and severe inflammatory bowel disease (IBD). This patient's leukocytes have undetectable dysbindin protein. We also identify dysregulated expression of several genes involved in activation of the adaptive immune response. This case underscores the emerging immunological consequences of dysbindin deficiency and suggests that DTNBP1 mutations may underlie some rare cases of very early onset IBD.

α-Dystrobrevin knockout mice have increased motivation for appetitive reward and altered brain cannabinoid receptor 1 expression.

α-Dystrobrevin (α-DB) is a major component of the dystrophin-associated protein complex (DAPC). Knockout (KO) of α-DB in the brain is associated with astrocytic abnormalities and loss of neuronal GABA receptor clustering. Mutations in DAPC proteins are associated with altered dopamine signaling and cognitive and psychiatric disorders, including schizophrenia. This study tested the hypothesis that motivation and associated underlying biological pathways are altered in the absence of α-DB expression. Male wildtype and α-DB KO mice were tested for measures of motivation, executive function and extinction in the rodent touchscreen apparatus. Subsequently, brain tissues were evaluated for mRNA and/or protein levels of dysbindin-1, dopamine transporter and receptor 1 and 2, mu opioid receptor 1 (mOR1) and cannabinoid receptor 1 (CB1). α-DB KO mice had significantly increased motivation for the appetitive reward, while measures of executive function and extinction were unaffected. No differences were observed between wildtype and KO animals on mRNA levels of dysbindin-1 or any of the dopamine markers. mRNA levels of mOR1were significantly decreased in the caudate-putamen and nucleus accumbens of α-DB KO compared to WT animals, but protein levels were unaltered. However, CB1 protein levels were significantly increased in the prefrontal cortex and decreased in the nucleus accumbens of α-DB KO mice. Triple-labelling immunohistochemistry confirmed that changes in CB1 were not specific to astrocytes. These results highlight a novel role for α-DB in the regulation of appetitive motivation that may have implications for other behaviours that involve the dopaminergic and endocannabinoid systems.

The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression.

Synaptic proteins and synaptic transmission are under homeostatic control, but the relationship between these two processes remains enigmatic. Here, we systematically investigated the role of E3 ubiquitin ligases, key regulators of protein degradation-mediated proteostasis, in presynaptic homeostatic plasticity (PHP). An electrophysiology-based genetic screen of 157 E3 ligase-encoding genes at the Drosophila neuromuscular junction identified thin, an ortholog of human tripartite motif-containing 32 (TRIM32), a gene implicated in several neurological disorders, including autism spectrum disorder and schizophrenia. We demonstrate that thin functions presynaptically during rapid and sustained PHP. Presynaptic thin negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready vesicles, largely independent of gross morphological defects. We provide genetic evidence that thin controls release through dysbindin, a schizophrenia-susceptibility gene required for PHP. Thin and Dysbindin localize in proximity within presynaptic boutons, and Thin degrades Dysbindin in vitro. Thus, the E3 ligase Thin links protein degradation-dependent proteostasis of Dysbindin to homeostatic regulation of neurotransmitter release.

Dysbindin-1A modulation of astrocytic dopamine and basal ganglia dependent behaviors relevant to schizophrenia.

The mechanisms underlying the dichotomic cortical/basal ganglia dopaminergic abnormalities in schizophrenia are unclear. Astrocytes are important non-neuronal modulators of brain circuits, but their role in dopaminergic system remains poorly explored. Microarray analyses, immunohistochemistry, and two-photon laser scanning microscopy revealed that Dys1 hypofunction increases the reactivity of astrocytes, which express only the Dys1A isoform. Notably, behavioral and electrochemical assessments in mice selectively lacking the Dys1A isoform unraveled a more prominent impact of Dys1A in behavioral and dopaminergic/D2 alterations related to basal ganglia, but not cortical functioning. Ex vivo electron microscopy and protein expression analyses indicated that selective Dys1A disruption might alter intracellular trafficking in astrocytes, but not in neurons. In agreement, Dys1A disruption only in astrocytes resulted in decreased motivation and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. These processes might have clinical relevance because the caudate, but not the cortex, of patients with schizophrenia shows a reduction of the Dys1A isoform. Therefore, we started to show a hitherto unknown role for the Dys1A isoform in astrocytic-related modulation of basal ganglia behavioral and dopaminergic phenotypes, with relevance to schizophrenia.

Protein Kinase B/Akt1 Phosphorylates Dysbindin-1A at Serine 10 to Regulate Neuronal Development.

Schizophrenia is a neurodevelopmental disorder with dendrite and dendritic spine dysfunction. Dysbindin-1, a protein decreased in the brains of schizophrenia patients, is involved in the development of dendrites and spines. However, it is still unclear how the role of dysbindin-1 in neuronal development is regulated. Here, we showed protein kinase B/Akt1, a serine/threonine kinase implicated in schizophrenia, phosphorylated dysbindin-1A at serine 10 (S10). S10 phosphorylation of dysbindin-1A was increased during postnatal neuronal and synapse development stage, and was enriched in postsynaptic densities (PSDs). Furthermore, overexpressing wild type or S10 phospho-mimic mutant (S10D), but not S10 phospho-dead mutant (S10A) of dysbindin-1A rescued the dendrite and spine deficits in dysbindin-1A knockdown neurons. These results indicate S10 phosphorylation of dysbindin-1A by Akt1 is essential for neuronal development, providing a potential regulation mechanism for dysbindin-1A in neuronal development.

Objective to identify and verify the regulatory mechanism of DTNBP1 as a prognostic marker for hepatocellular carcinoma.

Although the overall survival of hepatocellular carcinoma (HCC) patients has been significantly improved, prognostic clinical evaluation remains a substantial problem owing to the heterogeneity and complexity of tumor. A reliable and accurate predictive biomarker may assist physicians in better monitoring of patient treatment outcomes and follow the overall survival of patients. Accumulating evidence has revealed that DTNBP1 plays functional roles in cancer prognosis. Therefore, the expression and function of DTNBP1in HCC was systematically investigated in our study. The expression and prognostic value of DTNBP1 were investigated using the data from Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) cohorts and clinical samples. A series of cellular function assays were performed to elucidate the effect of DTNBP1 on cellular proliferation, apoptosis and metastasis. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment and Protein-protein interaction (PPI) network construction were performed to screen the genes with highest interaction scores with DTNBP1. Finally, the underlying mechanism was also analyzed using Gene Set Enrichment Analysis (GSEA) and confirmed using RT-qPCR and western blotting. DTNBP1 was upregulated in many types of cancers, especially in HCC. The DTNBP1 expression levels is associated with clinicopathologic variables and patient survival status. The differential expression of DTNBP1 could be used to determine the risk stratification of patients with HCC. DTNBP1 deficiency inhibited cell proliferation and metastasis, but promoted cell apoptosis. Mechanistically, DTNBP1 regulated the cell cycle progression through affecting the expression of cell cycle-related genes such as CDC25A, CCNE1, CDK2, CDC20, CDC25B, CCNB1, and CDK1. DTNBP1, which regulates the cell cycle progression, may be used as a prognostic marker for HCC.

Cortical copper transporter expression in schizophrenia: interactions of risk gene dysbindin-1.

Schizophrenia susceptibility factor dysbindin-1 is associated with cognitive processes. Downregulated dysbindin-1 expression is associated with lower expression of copper transporters ATP7A and CTR1, required for copper transport to the central nervous system. We measured dysbindin-1 isoforms-1A and -1BC, CTR1, and ATP7A via Western blots of the postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects (n = 28) and matched controls (n = 14). In addition, we subdivided the schizophrenia group by treatment status and comorbidity of alcohol use disorder (AUD) and assessed the relationships between proteins. Schizophrenia subjects exhibited similar protein levels to that of controls, with no effect of antipsychotic treatment. We observed a shift towards more dysbindin-1A expression in schizophrenia, as revealed by the ratio of dysbindin-1 isoforms. Dysbindin-1A expression was negatively correlated with ATP7A in schizophrenia, with no correlation present in controls. AUD subjects exhibited less dysbindin-1BC and CTR1 than those without AUD. Our results, taken together with previous data, suggest that alterations in dysbindin-1 and copper transporters are brain-region specific. For example, protein levels of ATP7A, dysbindin 1BC, and CTR1 are lower in the substantia nigra in schizophrenia subjects. AUD in the DLPFC was associated with lower protein levels of dysbindin-1 and CTR1. Changes in dysbindin-1 isoform ratio and relationships appear to be prevalent in the disease, potentially impacting symptomology.

Schizophrenia-associated dysbindin modulates axonal mitochondrial movement in cooperation with p150glued.

Mitochondrial movement in neurons is finely regulated to meet the local demand for energy and calcium buffering. Elaborate transport machinery including motor complexes is required to deliver and localize mitochondria to appropriate positions. Defects in mitochondrial transport are associated with various neurological disorders without a detailed mechanistic information. In this study, we present evidence that dystrobrevin-binding protein 1 (dysbindin), a schizophrenia-associated factor, plays a critical role in axonal mitochondrial movement. We observed that mitochondrial movement was impaired in dysbindin knockout mouse neurons. Reduced mitochondrial motility caused by dysbindin deficiency decreased the density of mitochondria in the distal part of axons. Moreover, the transport and distribution of mitochondria were regulated by the association between dysbindin and p150glued. Furthermore, altered mitochondrial distribution in axons led to disrupted calcium dynamics, showing abnormal calcium influx in presynaptic terminals. These data collectively suggest that dysbindin forms a functional complex with p150glued that regulates axonal mitochondrial transport, thereby affecting presynaptic calcium homeostasis.

Markers of copper transport in the cingulum bundle in schizophrenia.

Imaging and postmortem studies indicate that schizophrenia subjects exhibit abnormal connectivity in several white matter tracts, including the cingulum bundle. Copper chelators given to experimental animals damage myelin and myelin-producing oligodendrocytes, and the substantia nigra of schizophrenia subjects shows lower levels of copper, copper transporters, and copper-utilizing enzymes. This study aimed to elucidate the potential role of copper homeostasis in white matter pathology in schizophrenia. Protein levels of the copper transporters ATP7A and CTR1, and dysbindin-1, an upstream modulator of copper metabolism and schizophrenia susceptibility factor, were measured using Western blot analyses of the postmortem cingulum bundle of schizophrenia subjects (n=16) and matched controls (n=13). Additionally, the patient group was subdivided by treatment status: off- (n=8) or on-medication (n=8). Relationships between proteins from the current study were correlated among themselves and markers of axonal integrity previously measured in the same cohort. Schizophrenia subjects exhibited similar protein levels to controls, with no effect of antipsychotic treatment. The dysbindin-1A/1BC relationship was positive in controls and schizophrenia subjects; however, antipsychotic treatment appeared to reverse this relationship in a statistically different manner from that of controls and unmedicated subjects. The relationships between dysbindin-1A/neurofilament heavy and ATP7A/α-tubulin were positively correlated in the schizophrenia group that was significantly different from the lack of correlation in controls. Copper transporters and dysbindin-1 appear to be more significantly affected in the grey matter of schizophrenia subjects. However, the relationships among proteins in white matter may be more substantial and dependent on treatment status.

Abnormalities in the copper transporter CTR1 in postmortem hippocampus in schizophrenia: A subregion and laminar analysis.

Dysbindin-1 modulates copper transport, which is crucial for cellular homeostasis. Several brain regions implicated in schizophrenia exhibit decreased levels of dysbindin-1, which may affect copper homeostasis therein. Our recent study showed decreased levels of dysbindin-1, the copper transporter-1 (CTR1) and copper in the substantia nigra in schizophrenia, providing the first evidence of disrupted copper transport in schizophrenia. In the present study, we hypothesized that there would be lower levels of dysbindin-1 and CTR1 in the hippocampus in schizophrenia versus a comparison group. Using semi-quantitative immunohistochemistry for dysbindin1 and CTR1, we measured the optical density in a layer specific fashion in the hippocampus and entorhinal cortex in ten subjects with schizophrenia and ten comparison subjects. Both regions were richly immunolabeled for CTR1 and dysbindin1 in both groups. In the superficial layers of the entorhinal cortex, CTR1 immunolabeled neuropil and cells showed lower optical density values in patients versus the comparison group. In the molecular layer of the dentate gyrus, patients had higher optical density values of CTR1 versus the comparison group. The density and distribution of dysbindin-1 immunolabeling was similar between groups. These laminar specific alterations of CTR1 in schizophrenia suggest abnormal copper transport in those locations.

Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice.

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.

Ethologically based behavioural and neurochemical characterisation of mice with isoform-specific loss of dysbindin-1A in the context of schizophrenia.

Dysbindin-1 is implicated in several aspects of schizophrenia, including cognition and both glutamatergic and dopaminergic neurotransmission. Targeted knockout of dysbindin-1A (Dys-1A KO), the most abundant and widely expressed isoform in the brain, is associated with deficits in delay/interference-dependent working memory. Using an ethologically based approach, the following behavioural phenotypes were examined in Dys-1A KO mice: exploratory activity, social interaction, anxiety and problem-solving ability. Levels of monoamines and their metabolites were measured in striatum, hippocampus and prefrontal cortex using high-performance liquid chromatography with electrochemical detection. The ethogram of initial exploration in Dys-1A KO mice was characterised by increased rearing from a seated position; over subsequent habituation, stillness was decreased relative to wildtype. In a test of dyadic social interaction with an unfamiliar conspecific in a novel environment, female KO mice showed an increase in investigative social behaviours. Marble burying behaviour was unchanged. Using the puzzle-box test to measure general problem-solving performance, no effect of genotype was observed across nine trials of increasing complexity. Dys-1A KO demonstrated lower levels of 5-HT in ratio to its metabolite 5-HIAA in the prefrontal cortex. These studies elaborate the behavioural and neurochemical phenotype of Dys-1A KO mice, revealing subtle genotype-related differences in non-social and social exploratory behaviours and habituation of exploration in a novel environment, as well as changes in 5-HT activity in brain areas related to schizophrenia.

The behavioral and neurochemical characterization of a Drosophila dysbindin mutant supports the contribution of serotonin to schizophrenia negative symptoms.

Mutations in the dystrobrevin binding protein 1 (DTNBP1) gene that encodes for the dysbindin-1 protein, are associated with a higher risk for schizophrenia. Interestingly, individuals carrying high-risk alleles in this gene have been associated with an increased incidence of negative symptoms for the disease, which include anhedonia, avolition and social withdrawal. Here we evaluated behavioral and neurochemical changes in a hypomorphic Drosophila mutant for the orthologue of human Dysbindin-1, dysb1. Mutant dysb1 flies exhibit altered social space parameters, suggesting asocial behavior, accompanied by reduced olfactory performance. Moreover, dysb1 mutant flies show poor performance in basal and startle-induced locomotor activity. We also report a reduction in serotonin brain levels and changes in the expression of the Drosophila serotonin transporter (dSERT) in dysb1 flies. Our data show that the serotonin-releasing amphetamine derivative 4-methylthioamphetamine (4-MTA) modulates social spacing and locomotion in control flies, suggesting that serotonergic circuits modulate these behaviors. 4-MTA was unable to modify the behavioral deficiencies in mutant flies, which is consistent with the idea that the efficiency of pharmacological agents acting at dSERT depends on functional serotonergic circuits. Thus, our data show that the dysb1 mutant exhibits behavioral deficits that mirror some aspects of the endophenotypes associated with the negative symptoms of schizophrenia. We argue that at least part of the behavioral aspects associated with these symptoms could be explained by a serotonergic deficit. The dysb1 mutant presents an opportunity to study the molecular underpinnings of schizophrenia negative symptoms and reveals new potential targets for treatment of the disease.

Dysbindin promotes pancreatic ductal adenocarcinoma metastasis by activating NF-κB/MDM2 via miR-342-3p.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid tumours and has the highest cancer-related mortality rate. Despite intense investigation, the molecular mechanisms underlying the invasiveness and aetiology of PDAC remain elusive. MicroRNAs (miRNAs) are key regulators of tumour cell plasticity, but their roles in PDAC metastasis have not been characterized. Our early studies showed that dysbindin protein levels are elevated in PDAC patients compared with control individuals and that dysbindin upregulation elicits PDAC cell proliferation via the PI3K pathway. Here, we show that dysbindin promoted PDAC metastasis via the NF-κB/MDM2 signalling axis. Increased dysbindin levels correlated with aggressive features in PDAC, and the overexpression of dysbindin significantly promoted PDAC metastasis and invasion in vitro and in vivo. Surprisingly, dysbindin was identified as a direct target of miR-342-3p, which promotes NF-κB activation and PDAC metastasis. Thus, dysbindin-mediated NF-κB activation via miR-342-3p represents a context-dependent switch that enables PDAC cell proliferation and metastasis. Our data suggest that dysbindin and miR-342-3p are potential leads for the development of targeted therapy for PDAC.

Impaired copper transport in schizophrenia results in a copper-deficient brain state: A new side to the dysbindin story.

Objectives: Several schizophrenia brain regions exhibit decreased dysbindin. Dysbindin modulates copper transport crucial for myelination, monoamine metabolism and cellular homeostasis. Schizophrenia patients (SZP) exhibit increased plasma copper, while copper-decreasing agents produce schizophrenia-like behavioural and pathological abnormalities. Therefore, we sought to determine dysbindin and copper transporter protein expression and copper content in SZP.Methods: We studied the copper-rich substantia nigra (SN) using Western blot and inductively-coupled plasma mass spectrometry. We characterised specific protein domains of copper transporters ATP7A, CTR1, ATP7B and dysbindin isoforms 1 A and 1B/C in SZP (n = 15) and matched controls (n = 11), and SN copper content in SZP (n = 14) and matched controls (n = 11). As a preliminary investigation, we compared medicated (ON; n = 11) versus unmedicated SZP (OFF; n = 4).Results: SZP exhibited increased C terminus, but not N terminus, ATP7A. SZP expressed less transmembrane CTR1 and dysbindin 1B/C than controls. ON exhibited increased C terminus ATP7A protein versus controls. OFF exhibited less N terminus ATP7A protein than controls and ON, suggesting medication-induced rescue of the ATP7A N terminus. SZP exhibited less SN copper content than controls.Conclusions: These results provide the first evidence of disrupted copper transport in schizophrenia SN that appears to result in a copper-deficient state. Furthermore, copper homeostasis may be modulated by specific dysbindin isoforms and antipsychotic treatment.

Investigation of the roles of dysbindin-1 and SATB2 in the progression of Parkinson's disease.

OBJECTIVE: Parkinson's disease is a neurodegenerative disease that typically results in the loss of dopaminergic neurons, especially in an area of the brain known as the substantia nigra. Here, we investigated the roles of two important neuronal development proteins, dysbindin-1 and SATB2, at different stages of Parkinson's disease. MATERIALS AND METHODS: Using various concentrations of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we established the mouse models at initial and advanced stages of the Parkinson's disease. The pole and rotarod tests were used to assess behavioral response and motor function, respectively. Histology was used to assess the disease pathology. Immunohistochemistry and Western blotting were used to analyze dysbindin-1 and SATB2 expression levels. RESULTS: Compared with controls, the mice in the initial and advanced stages of Parkinson's disease required 2.3-fold and 3.8-fold longer to reach the floor in the pole test. Similarly, in the rotarod test, mice in the initial (168 ± 3.73 s) and advanced stages (91 ± 5.62 s) of Parkinson's disease were less able to maintain motor stability, compared with control mice (214 ± 4.18 s). The expression levels of dysbindin-1 and SATB2 in substantia nigra tissue from control mice were limited but were substantially increased (2.4-fold and 3.6-fold, respectively) in mice in the initial stage of the Parkinson's disease. However, in the mice in the advanced stage of Parkinson's disease, dysbindin-1 expression was 1.7-fold lower, and the SATB2 expression was 1.8-fold higher, than that in the control mice. CONCLUSIONS: The increased expression levels of dysbindin-1 and SATB2 in the initial stage of Parkinson's disease may be due to their protective roles. However, the reduced expression levels in the advanced stage of Parkinson's disease may contribute to irreversible neuronal degeneration.

Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95.

Fas plays a major role in regulating ligand-induced apoptosis in many cell types. It is well known that several cancers demonstrate reduced cell surface levels of Fas and thus escape a potential control system via ligand-induced apoptosis, although underlying mechanisms are unclear. Here we report that the endosome associated trafficking regulator 1 (ENTR1), controls cell surface levels of Fas and Fas-mediated apoptotic signalling. ENTR1 regulates, via binding to the coiled coil domain protein Dysbindin, the delivery of Fas from endosomes to lysosomes thereby controlling termination of Fas signal transduction. We demonstrate that ENTR1 is cleaved during Fas-induced apoptosis in a caspase-dependent manner revealing an unexpected interplay of apoptotic signalling and regulation of endolysosomal trafficking resulting in a positive feedback signalling-loop. Our data provide insights into the molecular mechanism of Fas post-endocytic trafficking and signalling, opening possible explanations on how cancer cells regulate cell surface levels of death receptors.

Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

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. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.