TY  - JOUR
AU  - Leliveld, S. R.
AU  - Bader, V.
AU  - Hendriks, P.
AU  - Prikulis, I.
AU  - Sajnani, G.
AU  - Requena, J. R.
AU  - Korth, C.
TI  - Insolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease
JO  - The journal of neuroscience
VL  - 28
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.
M1  - PreJuSER-62865
SP  - 3839 - 3845
PY  - 2008
N1  - Record converted from VDB: 12.11.2012
AB  - Disrupted-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.
KW  - Animals
KW  - Brain Chemistry
KW  - Cadaver
KW  - Carrier Proteins: metabolism
KW  - Cell Line, Tumor
KW  - Drug Interactions
KW  - Escherichia coli: metabolism
KW  - Humans
KW  - Ligands
KW  - Mice
KW  - Mice, Transgenic
KW  - Mood Disorders: genetics
KW  - Mood Disorders: metabolism
KW  - Nerve Tissue Proteins: chemistry
KW  - Nerve Tissue Proteins: metabolism
KW  - Phenotype
KW  - Proteome: isolation & purification
KW  - Recombinant Proteins: metabolism
KW  - Schizophrenia: genetics
KW  - Schizophrenia: metabolism
KW  - Solubility
KW  - Carrier Proteins (NLM Chemicals)
KW  - DISC1 protein, human (NLM Chemicals)
KW  - Ligands (NLM Chemicals)
KW  - NDEL1 protein, human (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - Proteome (NLM Chemicals)
KW  - Recombinant Proteins (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:18400883
UR  - <Go to ISI:>//WOS:000255012400003
DO  - DOI:10.1523/JNEUROSCI.5389-07.2008
UR  - https://juser.fz-juelich.de/record/62865
ER  -