Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome
Dyrk1A overexpression in immortalized hippocampal cells produces the neuropathological features of Down syndrome
复制标题
DOI：
10.1016/j.mcn.2007.07.007
复制
发表时间：
2007-10-01
影响因子：
3.5
通讯作者：
Chung, Kwang Chul
中科院分区：
文献类型：
--
作者：
Park, Joongkyu;Yang, Eun Jin;Chung, Kwang Chul
唐氏综合症（DS）是最常见的遗传性疾病，其特征是智力迟钝、先天性心脏异常和易患阿尔茨海默病（AD）。退行性椎体滑移患者的大脑发育与细胞凋亡升高和神经元分化异常有关。这些关键特征与人类密切相关。人类21号染色体唐氏综合征关键区域（DSCR）内的基因。脯氨酸定向丝氨酸/苏氨酸激酶dyrk1a在DSCR中被定位，参与细胞生长和胚胎后神经发生的控制。尽管Dyrk1A可能参与神经退行性变，但其与AD易感性和DS患者神经病理学的联系尚不清楚。在这里，我们报告了支持Dyrk1A与退行性椎体滑移神经病理之间相关性的证据。我们的研究结果表明，Dyrk1A与永生化海马祖细胞H19-7中的tau和淀粉样蛋白相互作用并直接磷酸化。此外，在过表达Dyrk1A的H19-7细胞中检测到tau包涵体的形成和β -淀粉样蛋白片段的增强生成。此外，这些细胞在血清剥夺条件下凋亡细胞死亡明显增加，并且在神经元分化方面也表现出缺陷。这些结果表明，Dyrk1A的上调可能导致DS患者ad样发病和异常的神经生物学特征。(c) 2007爱思唯尔公司版权所有。
Down syndrome (DS) is the most common genetic disorder, characterized by mental retardation, congenital heart abnormalities, and susceptibility to Alzheimer's disease (AD). Brain development of DS patients is associated with elevated apoptosis and abnormal neuronal differentiation. Those key features are closely associated with Man. genes mapped within Down syndrome critical region (DSCR) on human chromosome 21. Proline-directed serine/threonine kinase, Dyrk1A. is mapped within DSCR, and involved in the control of cell growth and postembryonic neurogenesis. Despite the potential involvement of Dyrk1A in neurodegeneration, its links to AD susceptibility and the neuropathology of DS patients are not yet clearly understood. Here, we report evidence supporting the correlation between Dyrk1A and neuropathology of DS. Our results show that Dyrk1A interacts with and directly phosphorylates tau and amyloid precursor protein in immortalized hippocampal progenitor H19-7 cells. In addition, the formation of tau inclusion and the enhanced generation of beta-amyloid fragment were detected in H19-7 cells that overexpressed Dyrk1A. Furthermore, these cells show a marked increase in apoptotic cell death under conditions of serum deprivation and also exhibit defects in neuronal differentiation. These results suggest that upregulation of Dyrk1A may cause AD-like pathogenesis and abnormal neurobiological features in DS patients. (c) 2007 Elsevier Inc. All rights reserved.