Topic
Dysbindin
About: Dysbindin is a research topic. Over the lifetime, 265 publications have been published within this topic receiving 16633 citations. The topic is also known as: BLOC1S8 & DBND.
Papers published on a yearly basis
Papers
TL;DR: This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry.
Abstract: This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.
2,013 citations
TL;DR: Family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by approximately 7 Mb, that are strongly associated with schizophrenia, and it is concluded that further investigation of dysbindin is warranted.
Abstract: Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length–polymorphism markers and of 17 SNP markers implicated two regions, separated by ∼7 Mb. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical P values produced by the program TRANSMIT were significant (P<.01) for a number of individual SNP markers, and most remained significant when the data were restricted to include only one affected offspring per nuclear family per extended pedigree; multiple three-marker haplotypes were highly significant (P=.008–.0001) under the restricted conditions. The pattern of linkage disequilibrium is consistent with the presence of more than one susceptibility allele, but this important issue is unresolved. The number of markers tested in the adjacent genes, all of which are negative, is not sufficient to rule out the possibility that the dysbindin gene is not the actual susceptibility gene, but this possibility appears to be very unlikely. We conclude that further investigation of dysbindin is warranted.
887 citations
TL;DR: In this paper, the authors identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1.
653 citations
TL;DR: In this paper, the authors found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P = 0.00028).
Abstract: Genetic variation in dysbindin (DTNBP1: dystrobrevin-binding protein 1) has recently been shown to be associated with schizophrenia. The dysbindin gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. We attempted to replicate this association in a Japanese sample of 670 patients with schizophrenia and 588 controls. We found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P = 0.00028). We then explored functions of dysbindin protein in primary cortical neuronal culture. Overexpression of dysbindin induced the expression of two pre-synaptic proteins, SNAP25 and synapsin I, and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in the reduction of pre-synaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in pre-synaptic machinery. The overexpression of dysbindin increased phosphorylation of Akt protein and protected cortical neurons against neuronal death due to serum deprivation and these effects were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin promotes neuronal viability through PI3-kinase-Akt signaling. Genetic variants associated with impairments of these functions of dysbindin could play an important role in the pathogenesis of schizophrenia.
382 citations
TL;DR: How disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits is discussed.
Abstract: Schizophrenia is a disabling mental illness that is now recognized as a neurodevelopmental disorder. It is likely that genetic risk factors interact with environmental perturbations to affect normal brain development and that this altered trajectory results in a combination of positive, negative, and cognitive symptoms. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype, has received great attention. Proper expression and regulation of NMDARs in the brain is critical for learning and memory processes as well as cortical plasticity and maturation. Evidence from both animal models and human studies implicates a dysfunction of NMDARs both in disease progression and symptoms of schizophrenia. Furthermore, mutations in many of the known genetic risk factors for schizophrenia suggest that NMDAR hypofunction is a convergence point for schizophrenia. In this review, we discuss how disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits. We review the shared signaling pathways among the schizophrenia susceptibility genes DISC1, neuregulin1, and dysbindin, focusing on the AKT/GSK3β pathway, and how their mutations and interactions can lead to NMDAR dysfunction during development. Additionally, we explore what open questions remain and suggest where schizophrenia research needs to move in order to provide mechanistic insight into the cause of NMDAR dysfunction, as well as generate possible new avenues for therapeutic intervention.
251 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 9 |
| 2020 | 8 |
| 2019 | 2 |
| 2018 | 5 |
| 2017 | 8 |
| 2016 | 10 |