Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs.

Abstract	DISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk SNPs impact on hippocampal structure and function. In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation such as fasciculation and elongation protein zeta-1 (FEZ1), platelet-activating factor acetylhydrolase, isoform Ib, PAFAH1B1 or lissencephaly 1 protein (LIS1) and nuclear distribution element-like (NUDEL). We hypothesized that altered expression of DISC1 and/or its molecular partners may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls. We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs. However, the expression of NUDEL, FEZ1 and LIS1 was each significantly reduced in the brain tissue from patients with schizophrenia and expression of each showed association with high-risk DISC1 polymorphisms. Although, many other DISC1 binding partners still need to be investigated, these data implicate genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.
Authors	Barbara K Lipska, Tricia Peters, Thomas M Hyde, Nader Halim, Cara Horowitz, Shruti Mitkus, Cynthia Shannon Weickert, Mitsuyuki Matsumoto, Akira Sawa, Richard E Straub, Radhakrishna Vakkalanka, Mary M Herman, Daniel R Weinberger, Joel E Kleinman
Journal	Human molecular genetics (Hum Mol Genet) Vol. 15 Issue 8 Pg. 1245-58 (Apr 15 2006) ISSN: 0964-6906 [Print] England
PMID	16510495 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References	Adaptor Proteins, Signal Transducing Antipsychotic Agents Carrier Proteins Cell Adhesion Molecules, Neuronal DISC1 protein, human DNA-Binding Proteins Extracellular Matrix Proteins FEZ1 protein, human LZTS1 protein, human Microtubule-Associated Proteins NDEL1 protein, human Nerve Tissue Proteins RNA, Messenger Reelin Protein Reln protein, rat Tumor Suppressor Proteins 1-Alkyl-2-acetylglycerophosphocholine Esterase PAFAH1B1 protein, human RELN protein, human Serine Endopeptidases
Topics	1-Alkyl-2-acetylglycerophosphocholine Esterase Adaptor Proteins, Signal Transducing Adolescent Adult Aged Aged, 80 and over Animals Antipsychotic Agents (metabolism, pharmacology) Carrier Proteins (genetics, metabolism) Cell Adhesion Molecules, Neuronal (genetics, metabolism) Child Child, Preschool Cohort Studies DNA-Binding Proteins (genetics, metabolism) Extracellular Matrix Proteins (genetics, metabolism) Female Hippocampus (immunology, metabolism) Humans Infant Male Microtubule-Associated Proteins (genetics, metabolism) Middle Aged Nerve Tissue Proteins (genetics, metabolism) Neurons (metabolism, pathology) Polymerase Chain Reaction Polymorphism, Single Nucleotide Prefrontal Cortex (drug effects, metabolism) Protein Binding (genetics) Protein Structure, Tertiary RNA, Messenger (metabolism) Rats Reelin Protein Schizophrenia (genetics, metabolism) Serine Endopeptidases (genetics, metabolism) Signal Transduction Tumor Suppressor Proteins (genetics, metabolism) Two-Hybrid System Techniques

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