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

Abstract

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.

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Acknowledgements

We thank David E Krantz and Desmond J Smith for critical reading of the manuscript, and Donna Crandal for help in the preparation of Figure 6. This work was supported, in part, by the National Institutes of Health grant HL068117 and an Independent Investigator Award from NARSAD: The Mental Health Research Association.

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Correspondence to C A Ghiani or E C Dell'Angelica.

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Ghiani, C., Starcevic, M., Rodriguez-Fernandez, I. et al. The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth. Mol Psychiatry 15, 204–215 (2010). https://doi.org/10.1038/mp.2009.58

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