Association of VSNL1 with schizophrenia, frontal cortical function, and biological significance for its gene product as a modulator of cAMP levels and neuronal morphology.
Association of VSNL1 with schizophrenia, frontal cortical function, and biological significance for its gene product as a modulator of cAMP levels and neuronal morphology.
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DOI：
10.1038/tp.2011.20
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发表时间：
2011-07-19
影响因子：
6.8
通讯作者：
Rujescu D
中科院分区：
文献类型：
--
作者：
Braunewell KH;Dwary AD;Richter F;Trappe K;Zhao C;Giegling I;Schönrath K;Rujescu D
我们报告了在《精神障碍诊断和统计手册-IV》(DSM-IV) 诊断为精神分裂症的患者样本中，与健康对照相比，VSNL1 基因（维西宁样 1）的单核苷酸多态性 (SNP) 与精神分裂症和额叶皮质功能之间的关联。此外，VSNL1 SNP 与威斯康星卡片分类测试（一种评估额叶皮质功能的指标）的表现相关。 VSNL1 基因产物 Visinin 样蛋白 1 (VILIP-1) 是神经元 EF 手 Ca2+ 传感器蛋白家族的成员。此前，VILIP-1 mRNA 和蛋白表达在动物模型和精神分裂症患者中被证明发生了改变。 VILIP-1 影响细胞质环磷酸腺苷 (cAMP) 水平、细胞迁移、胞吐过程和外周分化。这就提出了一个问题，与其他潜在的精神分裂症易感基因（例如 Disc1、PDE4B 和 Akt）类似，VSNL1 是否可能影响神经元中的 cAMP 信号传导和神经突生长。在分离的大鼠海马神经元中，与对照转染的细胞相比，VILIP-1 小干扰 RNA 敲低降低了 cAMP 水平并减少了树突分支。相反，VILIP-1过表达则产生相反的效果。在人多巴胺能神经元细胞系 SH-SY5Y 中也获得了类似的结果，其中腺苷酸环化酶抑制剂 2',5'-双脱氧腺苷和蛋白激酶 A 抑制剂 KT5720 减弱了对神经突分支和长度的影响。这些结果表明，VSNL1 SNP 与疾病和认知障碍的关联，以及先前观察到的 VILIP-1 蛋白表达的病理变化（可能发生在大脑发育过程中）可能导致精神分裂症中观察到的形态和功能缺陷。
We report an association of single-nucleotide polymorphisms (SNPs) for the VSNL1 gene (visinin-like 1) with schizophrenia and frontal cortical function in a sample of patients with Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) diagnoses of schizophrenia, compared with healthy controls. Moreover, VSNL1 SNPs were associated with performance in the Wisconsin Card Sorting Test, a measure for the assessment of frontal cortical function. The VSNL1 gene product, Visinin-like-protein-1 (VILIP-1), is a member of the neuronal EF-hand Ca2+-sensor protein family. Previously, VILIP-1 mRNA and protein expression were shown to be altered in animal models and in schizophrenia patients. VILIP-1 influences cytosolic cyclic adenosine mono phosphate (cAMP) levels, cell migration, exocytotic processes and differentiation in the periphery. This raises the question, whether, similar to other potential schizophrenia susceptibility genes such as Disc1, PDE4B and Akt, VSNL1 may affect cAMP signaling and neurite outgrowth in neurons. In dissociated rat hippocampal neurons, VILIP-1 small interfering RNA knockdown decreased cAMP levels and reduced dendrite branching, compared with control-transfected cells. In contrast, VILIP-1 overexpression had the opposite effect. Similar results have been obtained in the human dopaminergic neuronal cell line SH-SY5Y, where the effect on neurite branching and length was attenuated by the adenylyl cyclase inhibitor 2′,5′-dideoxyadenosine and the protein kinase A inhibitor KT5720. These results show that the association of VSNL1 SNPs with the disease and cognitive impairments, together with previously observed pathological changes in VILIP-1 protein expression, possibly occurring during brain development, may contribute to the morphological and functional deficits observed in schizophrenia.
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影响因子：
34.7
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1083/jcb.200507096
发表时间：
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期刊：
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