The pathogenic mechanism of dysbindin-1B toxic aggregation: BLOC-1 and intercellular vesicle trafficking

Abstract

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. In the brain, dysbindin-1 is primarily found as a subunit of biogenesis of lysosome-related organelles complex 1 (BLOC-1), which plays a role in intracellular vesicle trafficking. Therefore, we hypothesized that dysbindin-1B might impair the cognitive function of schizophrenia patients by co-aggregating with BLOC-1 subunits and disturbing the function of BLOC-1. In this study, we investigated the dominant-negative effect of dysbindin-1B on the BLOC-1 complex. We found that in multiple brain areas in Dys1B+/+ mice, the expression levels of soluble functional BLOC-1 subunits were decreased. Meanwhile, BLOC-1 subunits co-aggregated with dysbindin-1B-myc. Functional studies in primary cortical neurons further revealed the malfunction of BLOC-1 in intercellular vesicle trafficking in Dys1B+/+ mice. In addition, we used the Morris water maze task to investigate the effects of dysbindin-1B aggregation on cognition. The results demonstrated that Dys1B+/+ mice exhibited spatial learning and memory deficits, which were accompanied by the shrinkage of apical and basal dendritic branches and the loss of dendritic spines in hippocampal CA1 neurons, as demonstrated by Golgi staining. Taken together, the results of the present study suggest that dysbindin-1B toxic aggregation might impair cognition through a dominant-negative effect on BLOC-1.