Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia‐related protein

Hikita, Takao; Taya, Shinichiro; Fujino, Yasutaka; Taneichi-Kuroda, Setsuko; Ohta, Kanae; Tsuboi, Daisuke; Shinoda, Tomoyasu; Kuroda, Kensuke; Funahashi, Yasuhiro; Uraguchi-Asaki, Junko; Hashimoto, Ryota; Kaibuchi, Kozo

doi:10.1111/j.1471-4159.2009.06257.x

Cited by 26 publications

(36 citation statements)

References 51 publications

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“…Previously, an affinity chromatography-based PPI study was performed for the dysbindin in rat brain using the purified GST-tagged dysbindin as a bait to isolate dysbindin-binding proteins from the cytosol and P2 fraction. 65 Only dynamin-3 (DNM3) was identified in both the present and the previous analyses. The poor overlap between these two studies implies that protein complexes formed in vivo may not be able to be rearranged/reformed in vitro.…”

Section: Discussionsupporting

confidence: 49%

Dysbindin-Associated Proteome in the P2 Synaptosome Fraction of Mouse Brain

Han

Chen

et al. 2014

J. Proteome Res.

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The gene DTNBP1 encodes the protein dysbindin and is among the most promising and highly investigated schizophrenia-risk genes. Accumulating evidence suggests that dysbindin plays an important role in the regulation of neuroplasticity. Dysbindin was reported to be a stable component of BLOC-1 complex in the cytosol. However, little is known about the endogenous dysbindin-containing complex in the brain synaptosome. In this study, we investigated the associated proteome of dysbindin in the P2 synaptosome fraction of mouse brain. Our data suggest that dysbindin has three isoforms associating with different complexes in the P2 fraction of mouse brain. To facilitate immunopurification, BAC transgenic mice expressing a tagged dysbindin were generated, and 47 putative dysbindin-associated proteins, including all components of BLOC-1, were identified by mass spectrometry in the dysbindin-containing complex purified from P2. The interactions of several selected candidates, including WDR11, FAM91A1, snapin, muted, pallidin, and two proteasome subunits, PSMD9 and PSMA4, were verified by coimmunoprecipitation. The specific proteasomal activity is significantly reduced in the P2 fraction of the brains of the dysbindin-null mutant (sandy) mice. Our data suggest that dysbindin is functionally interrelated to the ubiquitin-proteasome system and offer a molecular repertoire for future study of dysbindin functional networks in brain.

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Section: Discussionsupporting

confidence: 49%

Dysbindin-Associated Proteome in the P2 Synaptosome Fraction of Mouse Brain

Han

Chen

et al. 2014

J. Proteome Res.

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“…In immortalized lymphocytes, it might be difficult to observe the effect of dysbindin-1 and NRG-1 gene expression on their neuron-specific functions, for example, the effect of dysbindin-1 on glutamate and dopamine release, 5,6,29 and on the formation of synaptic vesicles 30 and the effect of NRG-1 on N-methyl D-aspartate receptor hypofunction. 31 However, we might be able to determine the effect of dysbindin-1 and NRG-1 genes expression on their functions which are common in multiple tissues using immortalized lymphocytes, for example, the effect of dysbindin-1 on phosphatidylinositol 3 kinase-Akt signaling 29 and the effect of NRG-1 on ErbB-Akt signaling.…”

Section: Discussionmentioning

confidence: 99%

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

et al. 2011

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The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of dysbindin-1, NRG-1 and two other genes (NPY1R and GNAO1) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of dysbindin-1, NRG-1, NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the dysbindin-1 and NRG-1 genes. Journal of Human Genetics INTRODUCTIONSchizophrenia is a complex genetic disorder that is characterized by profound disturbances of cognition, emotion and social functioning. It affects B1% of the general population world wide. The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia, 1 and the dysbindin-1 gene is also associated with cognitive functions. [2][3][4] Furthermore, the Sandy mouse, which expresses no dysbindin-1, has been reported to have behavioral abnormalities, cognitive deficits and a synaptic dysfunction that is related to the pathophysiology of schizophrenia. [5][6][7] Identified risk variants of NRG-1 are associated with the reduced white matter volume that is observed in schizophrenic brains. 8 The NRG-1 gene spans 1.2 Mb 9 and gives rise to many structurally and functionally distinct isoforms, through alternative promoter usage. These isoforms are divided into three classic groups: 10 type I (previously known as acetylcholine receptor inducing activity, heregulin or neu differentiation factor), type II (glia growth factor) and type III (cysteine-rich domain containing), which are based on distinct amino termini. Additional NRG-1 5¢ exons have

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“…54 Only one of these four dysbindin interactomes links dysbindin with the adaptor complex AP-3, despite multiple biochemical, cell biology, and genetic evidence that these complexes interact in vivo and in vitro (Figure 1a). 55, 56, 57, 58, 59, 60, 61, 62 This deficiency in existing databases has immediate ramifications, as mutations in AP3B2 associated with ASD cannot be linked to schizophrenia through the BLOC-1 subunit dysbindin. 36, 37 AP3B2 is not an isolated instance.…”

Section: Neurodevelopmental Disorders: Boundary Definitions From Intementioning

confidence: 99%

Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes

et al. 2013

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Neurodevelopmental disorders such as intellectual disability, autism spectrum disorder and schizophrenia lack precise boundaries in their clinical definitions, epidemiology, genetics and protein–protein interactomes. This calls into question the appropriateness of current categorical disease concepts. Recently, there has been a rising tide to reformulate neurodevelopmental nosological entities from biology upward. To facilitate this developing trend, we propose that identification of unique proteomic signatures that can be strongly associated with patient's risk alleles and proteome-interactome-guided exploration of patient genomes could define biological mechanisms necessary to reformulate disorder definitions.

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Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia‐related protein

Cited by 26 publications

References 51 publications

Dysbindin-Associated Proteome in the P2 Synaptosome Fraction of Mouse Brain

Dysbindin-Associated Proteome in the P2 Synaptosome Fraction of Mouse Brain

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes

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