Abstract
Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world’s population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.
Highlights
Schizophrenia is an idiopathic mental illness occurring in 0.5–1% of the general population [1]
Dysbindin-1 is a protein encoded by dystrobrevin-binding protein 1 gene (DTNBP1), which is located on the short (p) arm of chromosome 6 at position 22.3 [30]
Besides the originally identified interacting protein dystrobrevin, it has been reported that dysbindin-1 interacts with many proteins, such as histone deacetylase 3 (HDAC3) [49], DNA-dependent protein kinase (DNA-PK) [42], nuclear factor-kappa B (NF-κB) [50], disrupted in schizophrenia 1 (DISC1) [51] and snapin [52]
Summary
Schizophrenia is an idiopathic mental illness occurring in 0.5–1% of the general population [1]. Schizophrenia-like symptoms include negative symptoms, such as reduced response to daily and social activities (motivation), depressive-like emotion or diminished expression of pleasure [3]. These symptoms impair patients’ daily functioning, and can be disabling [4]. It is interesting that the rates of developing schizophrenia were quite low and no difference was observed in the adoptive families of both affected and control groups [12]. These studies clearly indicate the important role of genetic factors in the pathogenesis of schizophrenia. We will examine the current understanding and evidence that are proposing dysbindin-1 involvement in schizophrenia and explore its potential as an intervention target for the treatment of schizophrenia
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