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Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation

机译：dysbindin-1B亚型在精神分裂症中的表达及其在聚集体形成中的倾向

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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.
机译：人类dysbindin-1基因（DTNBP1）的遗传变异与精神分裂症有关。作为选择性剪接的结果，人DTNBP1基因产生至少三种不同的蛋白质同工型，dysbindin-1A，-1B和-1C。大量的努力集中在dysbindin-1A上，dysbindin-1A是神经发育多个步骤中的重要角色。但是，其他同工型dysbindin-1B和dysbindin-1C尚未得到很好的表征。也没有与人类疾病有关。在这里，我们报告与健康对照组相比，偏执型精神分裂症患者DTNBP1b mRNA的表达增加。已经鉴定出位于内含子9 rs117610176中的单核苷酸多态性，并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dysbindin剪接同工型表现出不同的亚细胞分布，表明其不同的功能活性。 Dysbindin-1B在核周区域形成聚集体，而dysbindin-1A和-1C蛋白在细胞质中表现出分散的模式。 Dysbindin-1A与dysbindin-1B相互作用，当与dysbindin-1B共表达时被募集到总结构。此外，过度表达dysbindin-1B的皮质神经元显示神经突增生减少，这表明dysbindin-1B可能以显性负性方式干扰dysbindin-1A的功能。两者合计，我们的研究发现DTNBP1b表达与精神分裂症，除了其独特的生化和功能特性，以前未知的关联。

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