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.
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Expression of DISC1-interacting proteins is reduced in individuals carrying high-risk DISC1 SNPs, suggesting that DISC1 function might be affected in schizophrenia.
“the expression of DISC1-interacting proteins was reduced in individuals carrying high-risk DISC1 SNPs55, suggesting that DISC1 function might be affected in schizophrenia.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [55]
DISC1 mRNA levels appear unaffected in individuals with schizophrenia.
“Although DISC1 mRNA levels seem unaffected in individuals with schizophrenia55”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [55]
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- Authors
- Lipska, B. K., Peters, T., Hyde, T. M., Halim, N., Horowitz, C., Mitkus, S., Weickert, C. S., Matsumoto, M., Sawa, A., Straub, R. E., Vakkalanka, R., Herman, M. M., Weinberger, D. R., & Kleinman, J. E.
- Affiliations
- National Institutes of Health (US)
- Astellas Pharma (Japan) (JP)
- Johns Hopkins University (US)
- Corresponding author
- Lipska, Barbara K.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-03-01
- Volume
- 15
- Issue
- 8
- Pages
- 1245-1258
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2097088842
- Cited by
- 168
- References
- 51
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 11 · 2014: 11 · 2013: 5 · 2012: 8
- FWCI
- 12.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- schizophrenia, DISC1, FEZ1, LIS1, Nudel, PAFAH1B1, reelin, gene expression, schizophrenia risk genes, hippocampus, dorsolateral prefrontal cortex, postmortem brain, neuronal migration, neuronal differentiation
- MeSH terms
- Reelin Protein, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Carrier Proteins, Child, Child, Preschool, DNA-Binding Proteins, Female, Hippocampus, Humans, Infant, Male, Microtubule-Associated Proteins, Middle Aged, Nerve Tissue Proteins, Neurons, Protein Binding, RNA, Messenger, Schizophrenia, Serine Endopeptidases, Antipsychotic Agents, Cohort Studies, Signal Transduction, Cell Adhesion Molecules, Neuronal, Polymerase Chain Reaction, Extracellular Matrix Proteins, Prefrontal Cortex, Protein Structure, Tertiary, Polymorphism, Single Nucleotide, Two-Hybrid System Techniques, Tumor Suppressor Proteins, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Adaptor Proteins, Signal Transducing, Rats
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