Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome
Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome
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DOI：
10.1096/fj.07-104539
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发表时间：
2008-09-01
期刊：
影响因子：
4.8
通讯作者：
Gong, Cheng-Xin
中科院分区：
文献类型：
--
作者：
Liu, Fei;Liang, Zhihou;Gong, Cheng-Xin
患有唐氏综合症（DS）的成人大脑中会出现阿尔茨海默氏神经原纤维变性，但潜在的分子机制尚不清楚。在此，我们报告称，由于 21 三体性，双特异性酪氨酸磷酸化和调节激酶 1A (Dyrk1A) 基因的额外副本的存在导致 DS 脑中 Dyrk1A 过度表达和激酶活性升高。 Dyrk1A 在多个位点磷酸化 tau，并且这些位点在成人 DS 大脑中过度磷酸化。 Dyrk1A 对 tau 的磷酸化引发了糖原合酶激酶 3 beta (GSK-3 beta) 的进一步磷酸化。 Dyrk1A 诱导的 tau 磷酸化抑制 tau 的生物活性并促进其自我聚集。在 Ts65Dn 小鼠大脑中，Dyrk1A 基因的额外拷贝导致 Dyrk1A 表达和活性增加，并导致 tau 磷酸化增加。这些发现有力地表明了 DS 大脑中 Dyrk1A 的过度表达通过过度磷酸化 tau 导致神经原纤维变性的新机制。
Adults with Down syndrome (DS) develop Alzheimer neurofibrillary degeneration in the brain, but the underlying molecular mechanism is unknown. Here, we report that the presence of an extra copy of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene due to trisomy 21 resulted in overexpression of Dyrk1A and elevated kinase activity in DS brain. Dyrk1A phosphorylated tau at several sites, and these sites were hyperphosphorylated in adult DS brains. Phosphorylation of tau by Dyrk1A primed its further phosphorylation by glycogen synthase kinase-3 beta (GSK-3 beta). Dyrk1A-induced tau phosphorylation inhibited tau's biological activity and promoted its self-aggregation. In Ts65Dn mouse brain, an extra copy of the Dyrk1A gene caused increased expression and activity of Dyrk1A and resulted in increased tau phosphorylation. These findings strongly suggest a novel mechanism by which the overexpression of Dyrk1A in DS brain causes neurofibrillary degeneration via hyperphosphorylating tau.