Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A) Enhances Tau Expression
Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A) Enhances Tau Expression
复制标题
双特异性酪氨酸磷酸化调节激酶 1A (Dyrk1A) 增强 Tau 表达
DOI：
10.3233/jad-130824
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发表时间：
2013-01-01
影响因子：
4
通讯作者：
Liu, Fei
中科院分区：
文献类型：
--
作者：
Qian, Wei;Jin, Nana;Liu, Fei
微管相关蛋白tau被发现在阿尔茨海默病和相关的tauopathy患者的大脑中积累和聚集。双特异性酪氨酸-磷酸化调节激酶1A(Dyrk1A)在唐氏综合征中过度表达，可能在该病tau病理的早期发病中起关键作用。为了研究Dyrk1A对tau蛋白表达的影响，我们在HEK-293FT细胞中共表达了不同亚型的tau蛋白，并分别用RT-PCR和Western blotts方法检测了tau蛋白的表达水平。我们进一步研究了Dyrk1a对tau基因表达的调控机制。我们发现Dyrk1A以剂量依赖的方式增强tau的表达。这种增强并不需要Dyrk1A的激酶活性。与不含外显子10的异构体相比，Dyrk1A能更大程度地促进含有外显子10的tau异构体的表达。神经细胞中内源性tau的表达也受Dyrk1A的调节，并且由于16号染色体的部分三体，高表达Dyrk1A的Ts65Dn小鼠的脑组织中tau水平升高。Dyrk1A不能促进tau基因的转录，但增加了tau基因的稳定性。这些结果表明，Dyrk1A通过稳定其mRNA来增强tau的表达，并为tau的表达调控和tau病的分子机制提供了新的见解。
Microtubule-associated protein tau is found to be accumulated and aggregated in the brains of individuals with Alzheimer's disease and related tauopathies. Dual-specificity tyrosine-phosphorylation regulated kinase 1A (Dyrk1A) is overexpressed in Down syndrome and may play a critical role in the early onset of tau pathology in this disease. To investigate the effect of Dyrk1A on tau expression, we co-expressed different isoforms of tau with Dyrk1A in HEK-293FT cells and measured the mRNA and protein levels of tau using RT-PCR and Western blots, respectively. We further investigated the mechanism of regulation of tau expression by Dyrk1A. We found that Dyrk1A enhanced tau expression in a dose-dependent manner. The enhancement did not require the kinase activity of Dyrk1A. Dyrk1A increased the expression of tau isoforms containing exon 10 to a larger extent than isoforms lacking exon 10. The expression of endogenous tau in neuronal cells was also regulated by Dyrk1A, and increased tau levels were found in the brains of Ts65Dn mice that overexpress Dyrk1A due to partial trisomy of chromosome 16. Dyrk1A did not enhance tau gene transcription, but increased tau mRNA stability. These results suggest that Dyrk1A enhances tau expression by stabilizing its mRNA and provides a novel insight into the regulation of tau expression and a molecular mechanism of tauopathies.