Study On The Pathogenesis Of Schizophrenia By Dysbindin-1B Toxic Protein Precipitation

DTNBP1, encoding dysbindin-1, is associated with cognitive impairments, including memory deficits.Genetic evidenceindicates that the C allele of rs117610176 leads to increased mRNA splicing of DTNBP1bin patients with paranoid schizophrenia. In addition, dysbindin-1B, rather than dysbindin-1A/C, has the tendency of toxic aggregation and in postmortem brains,dysbindin-1B not only aggregates alone, but also co-aggregates proteins interacting with it.However, the pathogenic mechanism of the dysbindin-1B toxic aggregation remains unknown. A hint derives from biogenesis of lysosome-related organelles complex 1 (BLOC-1), which, as a dysbindin-containing complex, plays a role in synaptic vesicle trafficking and it leads us to ask whether dysbindin-1B impairs 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 exerted by dysbindin-1B to BLOC-1 complex.We found thatin multiple brain areas of Dys1B+/+ mice, the expression level ofsoluble functional BLOC-1 subunits were decreased. Meanwhile, BLOC-1 subunitswere provedto be co-aggregated with dysbindin-1 B-myc. Functional studies in primary cortical neurons further revealed the malfunctionof BLOC-1 in vesicle trafficking in Dys1B+/+ mice. In addition, we conducted Morris water maze tasks to investigate the effects of dysbindin-1B aggregation on cognition.The results demonstrated that the Dys1B+/+ mice presented spatial learning and memory deficits, which is further proved by the shrinkage of apical and basal branches and the loss of the dendritic spine in the hippocampal CA1 neurons by Golgi staining. Taken together, the present study suggested that dysbindin-1B toxic aggregation may impair the cognition by disturbing the expression of BLOC-1 subunits and the synaptic vesicle trafficking.