Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs
Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs
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DOI：
10.1093/hmg/ddl040
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发表时间：
2006-04-15
影响因子：
3.5
通讯作者：
Kleinman, JE
中科院分区：
文献类型：
--
作者：
Lipska, BK;Peters, T;Kleinman, JE
DISC 1已被确定为精神分裂症易感基因的基础上连锁和SNP关联的研究和临床数据表明，风险SNP影响海马结构和功能。在细胞和动物模型中，C-末端截短的DISC 1破坏细胞内转运、神经结构和迁移，这可能是因为它不能与参与神经元分化的结合伴侣相互作用，例如成束和延伸蛋白zeta-1（FEZ 1）、血小板活化因子乙酰水解酶、同种型Ib、PAFAH 1B 1或无脑畸形1蛋白（LIS 1）和核分布元件样（NUDEL）。我们假设DISC 1和/或其分子伴侣的表达改变可能是其在精神分裂症中的致病作用的基础，并解释其遗传相关性。我们研究了DISC 1和这些选定的结合伙伴，以及reelin，在相关的信号通路中的蛋白质，在海马和背外侧前额叶皮层的死后人脑精神分裂症患者和对照组的表达。我们发现DISC 1或reelin mRNA在精神分裂症中的表达没有差异，并且与先前确定的风险DISC 1 SNP没有关联。然而，NUDEL、FEZ 1和LIS 1的表达在精神分裂症患者的脑组织中均显著降低，并且每种表达均显示与高风险DISC 1多态性相关。虽然，许多其他DISC 1结合伙伴仍然需要调查，这些数据牵连在精神分裂症的病理生理DISC 1分子通路的遗传连锁异常。
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.