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000062865 0247_ $$2DOI$$a10.1523/JNEUROSCI.5389-07.2008
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000062865 084__ $$2WoS$$aNeurosciences
000062865 1001_ $$0P:(DE-Juel1)VDB72260$$aLeliveld, S. R.$$b0$$uFZJ
000062865 245__ $$aInsolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease
000062865 260__ $$aWashington, DC$$bSoc.$$c2008
000062865 300__ $$a3839 - 3845
000062865 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000062865 440_0 $$03603$$aJournal of Neuroscience$$v28$$x0270-6474$$y15
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000062865 520__ $$aDisrupted-in-schizophrenia 1 (DISC1) and other genes have been identified recently as potential molecular players in chronic psychiatric diseases such as affective disorders and schizophrenia. A molecular mechanism of how these genes may be linked to the majority of sporadic cases of these diseases remains unclear. The chronic nature and irreversibility of clinical symptoms in a subgroup of these diseases prompted us to investigate whether proteins corresponding to candidate genes displayed subtle features of protein aggregation. Here, we show that in postmortem brain samples of a distinct group of patients with phenotypes of affective disorders or schizophrenia, but not healthy controls, significant fractions of DISC1 could be identified as cold Sarkosyl-insoluble protein aggregates. A loss-of-function phenotype could be demonstrated for insoluble DISC1 through abolished binding to a key DISC1 ligand, nuclear distribution element 1 (NDEL1): in human neuroblastoma cells, DISC1 formed expression-dependent, detergent-resistant aggregates that failed to interact with endogenous NDEL1. Recombinant (r) NDEL1 expressed in Escherichia coli selectively bound an octamer of an rDISC1 fragment but not dimers or high molecular weight multimers, suggesting an oligomerization optimum for molecular interactions of DISC1 with NDEL1. For DISC1-related sporadic psychiatric disease, we propose a mechanism whereby impaired cellular control over self-association of DISC1 leads to excessive multimerization and subsequent formation of detergent-resistant aggregates, culminating in loss of ligand binding, here exemplified by NDEL1. We conclude that the absence of oligomer-dependent ligand interactions of DISC1 can be associated with sporadic mental disease of mixed phenotypes.
000062865 536__ $$0G:(DE-Juel1)FUEK409$$2G:(DE-HGF)$$aFunktion und Dysfunktion des Nervensystems$$cP33$$x0
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000062865 650_2 $$2MeSH$$aAnimals
000062865 650_2 $$2MeSH$$aBrain Chemistry
000062865 650_2 $$2MeSH$$aCadaver
000062865 650_2 $$2MeSH$$aCarrier Proteins: metabolism
000062865 650_2 $$2MeSH$$aCell Line, Tumor
000062865 650_2 $$2MeSH$$aDrug Interactions
000062865 650_2 $$2MeSH$$aEscherichia coli: metabolism
000062865 650_2 $$2MeSH$$aHumans
000062865 650_2 $$2MeSH$$aLigands
000062865 650_2 $$2MeSH$$aMice
000062865 650_2 $$2MeSH$$aMice, Transgenic
000062865 650_2 $$2MeSH$$aMood Disorders: genetics
000062865 650_2 $$2MeSH$$aMood Disorders: metabolism
000062865 650_2 $$2MeSH$$aNerve Tissue Proteins: chemistry
000062865 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000062865 650_2 $$2MeSH$$aPhenotype
000062865 650_2 $$2MeSH$$aProteome: isolation & purification
000062865 650_2 $$2MeSH$$aRecombinant Proteins: metabolism
000062865 650_2 $$2MeSH$$aSchizophrenia: genetics
000062865 650_2 $$2MeSH$$aSchizophrenia: metabolism
000062865 650_2 $$2MeSH$$aSolubility
000062865 650_7 $$00$$2NLM Chemicals$$aCarrier Proteins
000062865 650_7 $$00$$2NLM Chemicals$$aDISC1 protein, human
000062865 650_7 $$00$$2NLM Chemicals$$aLigands
000062865 650_7 $$00$$2NLM Chemicals$$aNDEL1 protein, human
000062865 650_7 $$00$$2NLM Chemicals$$aNerve Tissue Proteins
000062865 650_7 $$00$$2NLM Chemicals$$aProteome
000062865 650_7 $$00$$2NLM Chemicals$$aRecombinant Proteins
000062865 650_7 $$2WoSType$$aJ
000062865 65320 $$2Author$$apsychiatric disease
000062865 65320 $$2Author$$adepression
000062865 65320 $$2Author$$abipolar disorder
000062865 65320 $$2Author$$amultimerization
000062865 65320 $$2Author$$aprotein conformational disease
000062865 65320 $$2Author$$aprotein aggregation
000062865 7001_ $$0P:(DE-HGF)0$$aBader, V.$$b1
000062865 7001_ $$0P:(DE-HGF)0$$aHendriks, P.$$b2
000062865 7001_ $$0P:(DE-HGF)0$$aPrikulis, I.$$b3
000062865 7001_ $$0P:(DE-HGF)0$$aSajnani, G.$$b4
000062865 7001_ $$0P:(DE-HGF)0$$aRequena, J. R.$$b5
000062865 7001_ $$0P:(DE-HGF)0$$aKorth, C.$$b6
000062865 773__ $$0PERI:(DE-600)1475274-8$$a10.1523/JNEUROSCI.5389-07.2008$$gVol. 28, p. 3839 - 3845$$p3839 - 3845$$q28<3839 - 3845$$tThe @journal of neuroscience$$v28$$x0270-6474$$y2008
000062865 8567_ $$uhttp://dx.doi.org/10.1523/JNEUROSCI.5389-07.2008
000062865 8564_ $$uhttps://juser.fz-juelich.de/record/62865/files/3839.full.pdf$$yOpenAccess
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