Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome
Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome
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DOI：
10.1016/j.neulet.2006.11.026
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发表时间：
2007-02-08
影响因子：
2.5
通讯作者：
Wegiel, Jerzy
中科院分区：
文献类型：
--
作者：
Dowjat, Wieslaw K.;Adayev, Tatyana;Wegiel, Jerzy
唐氏综合症（DS）是最常见的与智力迟钝（MR）相关的遗传性疾病。据认为，许多DS的表型特征源于位于21号染色体三倍区一组基因的增强表达。在这些基因中，DYRK1A编码双特异性脯氨酸定向丝氨酸/treonine激酶，正如动物研究所证明的那样，它可能导致DS的认知缺陷。这种贡献是否可以通过DS受试者大脑中DYRK1A蛋白水平的升高来发挥，是本研究的主要目标。DYRK1A蛋白的水平通过Western blotting在包括大脑、小脑皮层和白质在内的6个大脑结构中进行测量。这项研究涉及了大量的DS研究对象和年龄匹配的对照，代表了不同年龄、性别和种族的婴儿和成年人。本研究还纳入了DS动物模型三体Ts65Dn小鼠。在三体小鼠和DS受试者中，DYRK1A蛋白的脑表达水平增加了约1.5倍，表明该蛋白以基因剂量依赖性的方式过表达。唯一的例外是婴儿组，在这一组中，没有增强表明存在一种发育调节机制。我们发现DYRK1A存在于每个分析的结构中，与年龄无关。DYRK1A在成人大脑中的广泛存在和组成性表达表明，该激酶在成人中枢神经系统中发挥着重要但不同的发育作用。这也意味着DYRK1A在DS中的过表达可能与这些个体在其整个生命周期中的MR状态有关。2006爱思唯尔爱尔兰有限公司版权所有。
Down syndrome (DS) is the most common genetic disorder associated with mental retardation (MR). It is believed that many of the phenotypic features of DS stem from enhanced expression of a set of genes located within the triplicated region on chromosome 21. Among those genes is DYRK1A encoding dual-specificity proline-directed serine/treonine kinase, which, as documented by animal studies, can potentially contribute to cognitive deficits in DS. Whether this contribution can be exerted through elevated levels of DYRK1A protein in the brain of DS subjects was the main goal of the present study. The levels of DYRK1A protein were measured by Western blotting in six brain structures that included cerebral and cerebellar cortices and white matter. The study involved large cohorts of DS subjects and age-matched controls representing infants and adults of different age, gender and ethnicity. Trisomic Ts65Dn mice, an animal model of DS, were also included in the study. Both in trisomic mice and in DS subjects, the brain levels of DYRK1A protein were increased approximately 1.5-fold, indicating that this protein is overexpressed in gene dosage-dependent manner. The exception was an infant group, in which there was no enhancement suggesting the existence of a developmentally regulated mechanism. We found DYRK1A to be present in every analyzed structure irrespective of age. This widespread occurrence and constitutive expression of DYRK1A in adult brain suggest an important, but diverse from developmental role played by this kinase in adult central nervous system. It also implies that overexpression of DYRK1A in DS may be potentially relevant to MR status of these individuals during theirentire life span. (c) 2006 Elsevier Ireland Ltd. All rights reserved.