TY - JOUR
T1 - Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs
AU - Lipska, Barbara K.
AU - Peters, Tricia
AU - Hyde, Thomas M.
AU - Halim, Nader
AU - Horowitz, Cara
AU - Mitkus, Shruti
AU - Weickert, Cynthia Shannon
AU - Matsumoto, Mitsuyuki
AU - Sawa, Akira
AU - Straub, Richard E.
AU - Vakkalanka, Radhakrishna
AU - Herman, Mary M.
AU - Weinberger, Daniel R.
AU - Kleinman, Joel E.
N1 - Funding Information:
We would like to thank Dr Llewellyn L. Bigelow and Mrs Amy Deep-Soboslay for their contribution to procurement of brain tissue and postmortem clinical characterization of subjects, Drs Koko Ishizuka and Naoya Sawamura for their help with DISC1 antibody characterization and purification, Mrs Yeva Snitkovsky, and Mr Robert Fatula for their excellent technical assistance. Most importantly, we thank the families of the deceased for the donations of brain tissue, and their time and effort devoted to the consent process and interviews, and the staff of the Offices of the Chief Medical Examiner of District of Columbia and of Northern Virginia for their assistance. This research was supported by the Intramural Program of the National Institutes of Health, NIMH.
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddl040
DO - 10.1093/hmg/ddl040
M3 - Article
C2 - 16510495
AN - SCOPUS:33645828206
SN - 0964-6906
VL - 15
SP - 1245
EP - 1258
JO - Human molecular genetics
JF - Human molecular genetics
IS - 8
ER -