The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis

Gigantic retroperitoneal hematoma as a complication of anticoagulation therapy with heparin in therapeutic doses: a case report

<p>Abstract</p> <p>Introduction</p> <p>Spontaneous retroperitoneal hemorrhage is a distinct clinical entity that can present as a rare life-threatening event characterized by sudden onset of bleeding into the retroperitoneal space, occurring in association with bleeding disorders, intratumoral bleeding, or ruptures of any retroperitoneal organ or aneurysm. The spontaneous form is the most infrequent retroperitoneal hemorrhage, causing significant morbidity and representing a diagnostic challenge.</p> <p>Case presentation</p> <p>We report the case of a patient with coronary artery disease who presented with transient ischemic attack, in whom anticoagulant therapy with heparin precipitated a massive spontaneous atraumatic retroperitoneal hemorrhage (with international normalized ratio 2.4), which was treated conservatively.</p> <p>Conclusion</p> <p>Delay in diagnosis is potentially fatal and high clinical suspicion remains crucial. Finally, it is a matter of controversy whether retroperitoneal hematomas should be surgically evacuated or conservatively treated and the final decision should be made after taking into consideration patient's general condition and the possibility of permanent femoral or sciatic neuropathy due to compression syndrome.</p

Health and Pleasure in Consumers' Dietary Food Choices: Individual Differences in the Brain's Value System

Taking into account how people value the healthiness and tastiness of food at both the behavioral and brain levels may help to better understand and address overweight and obesity-related issues. Here, we investigate whether brain activity in those areas involved in self-control may increase significantly when individuals with a high body-mass index (BMI) focus their attention on the taste rather than on the health benefits related to healthy food choices. Under such conditions, BMI is positively correlated with both the neural responses to healthy food choices in those brain areas associated with gustation (insula), reward value (orbitofrontal cortex), and self-control (inferior frontal gyrus), and with the percent of healthy food choices. By contrast, when attention is directed towards health benefits, BMI is negatively correlated with neural activity in gustatory and reward-related brain areas (insula, inferior frontal operculum). Taken together, these findings suggest that those individuals with a high BMI do not necessarily have reduced capacities for self-control but that they may be facilitated by external cues that direct their attention toward the tastiness of healthy food. Thus, promoting the taste of healthy food in communication campaigns and/or food packaging may lead to more successful self-control and healthy food behaviors for consumers with a higher BMI, an issue which needs to be further researched

Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes

BackgroundDysbindin, a cytoplasmic protein long known to function in the biogenesis of specialized lysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadly expressed, and dopamine receptors are members of the large family of G protein-coupled receptors (GPCRs) that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigated the cellular basis of this regulation.Methodology/principal findingsWe used RNA interference to deplete endogenous dysbindin in HEK293 and HeLa cells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post-endocytic sorting function explained the minimal effect of dysbindin depletion on D1 receptors, which recycle efficiently and traverse the lysosomal pathway to only a small degree. Moreover, dysbindin regulated the delta opioid receptor, a more distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal trafficking of all signaling receptors, however, as its depletion did not detectably affect down-regulation of the EGF receptor tyrosine kinase. Dysbindin co-immunoprecipitated with GASP-1 (or GPRASP-1), a cytoplasmic protein shown previously to modulate lysosomal trafficking of D2 dopamine and delta opioid receptors by direct interaction, and with HRS that is a core component of the conserved ESCRT machinery mediating lysosome biogenesis and sorting.Conclusions/significanceThese results identify a distinct, and potentially widespread function of dysbindin in promoting the sorting of specific GPCRs to lysosomes after endocytosis

The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis