We conclude that the absence of oligomer-dependent ligand interactions of DISC1 can be associated with sporadic mental disease of mixed phenotypes.
The Journal of Neuroscience, April 9, 2008, 28(15):3839-3845; doi:10.1523/JNEUROSCI.5389-07.2008
Neurobiology of Disease
Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease
S. Rutger Leliveld,1,2 Verian Bader,1 Philipp Hendriks,1 Ingrid Prikulis,1 Gustavo Sajnani,3 Jesús R. Requena,3 and Carsten Korth1
1Department of Neuropathology, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany, 2Department of Molecular Biophysics-II, Forschungszentrum Jülich, 52425 Jülich, Germany, and 3Department of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
Correspondence should be addressed to Dr. Carsten Korth, Department of Neuropathology, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Email: ckorth@uni-duesseldorf.de
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.
Key words: psychiatric disease; depression; bipolar disorder; multimerization; protein conformational disease; protein aggregation
Neurobiology of Disease
Insolubility of Disrupted-in-Schizophrenia 1 Disrupts Oligomer-Dependent Interactions with Nuclear Distribution Element 1 and Is Associated with Sporadic Mental Disease
S. Rutger Leliveld,1,2 Verian Bader,1 Philipp Hendriks,1 Ingrid Prikulis,1 Gustavo Sajnani,3 Jesús R. Requena,3 and Carsten Korth1
1Department of Neuropathology, Heinrich Heine University of Düsseldorf, 40225 Düsseldorf, Germany, 2Department of Molecular Biophysics-II, Forschungszentrum Jülich, 52425 Jülich, Germany, and 3Department of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
Correspondence should be addressed to Dr. Carsten Korth, Department of Neuropathology, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Email: ckorth@uni-duesseldorf.de
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.
Key words: psychiatric disease; depression; bipolar disorder; multimerization; protein conformational disease; protein aggregation
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