Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation.
Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation.
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精神分裂症中 Dysbindin-1B 亚型表达增加及其形成攻击体的倾向
DOI：
10.1038/celldisc.2015.32
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发表时间：
2015
期刊：
影响因子：
33.5
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Xu Y;Sun Y;Ye H;Zhu L;Liu J;Wu X;Wang L;He T;Shen Y;Wu JY;Xu Q
人类异联会蛋白1基因（DTNBP1）的遗传变异与精神分裂症有关。由于选择性剪接，人类DTNBP1基因至少产生三种不同的蛋白质异构体，即异联会蛋白 - 1A、 - 1B和 - 1C。大量的研究工作集中在异联会蛋白 - 1A上，它在神经发育的多个阶段都起着重要作用。然而，其他异构体，即异联会蛋白 - 1B和异联会蛋白 - 1C尚未得到很好的表征，也未发现与人类疾病有关。在此我们报道，与健康对照组相比，偏执型精神分裂症患者中DTNBP1b mRNA的表达增加。位于内含子9的一个单核苷酸多态性rs117610176已被确定与偏执型精神分裂症有关，其C等位基因导致DTNBP1b mRNA剪接增加。我们的数据表明，不同的异联会蛋白剪接异构体呈现出不同的亚细胞分布，这表明它们具有不同的功能活性。异联会蛋白 - 1B在核周区域形成聚集体，而异联会蛋白 - 1A和 - 1C蛋白在细胞质中呈现弥散分布模式。异联会蛋白 - 1A与异联会蛋白 - 1B相互作用，当与异联会蛋白 - 1B共表达时会被招募到聚集体结构中。此外，过表达异联会蛋白 - 1B的皮质神经元显示出神经突生长减少，这表明异联会蛋白 - 1B可能以显性负性方式干扰异联会蛋白 - 1A的功能。综上所述，我们的研究揭示了DTNBP1b表达除了其独特的生化和功能特性外，还与精神分裂症存在先前未知的关联。
Genetic variations in the human dysbindin-1 gene (DTNBP1) have been associated with schizophrenia. As a result of alternative splicing, the human DTNBP1 gene generates at least three distinct protein isoforms, dysbindin-1A,-1B and-1C. Significant effort has focused on dysbindin-1A, an important player in multiple steps of neurodevelopment. However, the other isoforms, dysbindin-1B and dysbindin-1C have not been well characterized. Nor have been associated with human diseases. Here we report an increase in expression of DTNBP1b mRNA in patients with paranoid schizophrenia as compared with healthy controls. A single-nucleotide polymorphism located in intron 9, rs117610176, has been identified and associated with paranoid schizophrenia, and its C allele leads to an increase of DTNBP1b mRNA splicing. Our data show that different dysbindin splicing isoforms exhibit distinct subcellular distribution, suggesting their distinct functional activities. Dysbindin-1B forms aggresomes at the perinuclear region, whereas dysbindin-1A and-1C proteins exhibit diffused patterns in the cytoplasm. Dysbindin-1A interacts with dysbindin-1B, getting recruited to the aggresome structure when co-expressed with dysbindin-1B. Moreover, cortical neurons over-expressing dysbindin-1B show reduction in neurite outgrowth, suggesting that dysbindin-1B may interfere with dysbindin-1A function in a dominant-negative manner. Taken together, our study uncovers a previously unknown association of DTNBP1b expression with schizophrenia in addition to its distinct biochemical and functional properties.