Regulation of alternative splicing of tau exon 10 by 9G8 and Dyrk1A.
Regulation of alternative splicing of tau exon 10 by 9G8 and Dyrk1A.
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9G8 和 Dyrk1A 对 tau 外显子 10 选择性剪接的调节
DOI：
10.1016/j.neurobiolaging.2010.11.021
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发表时间：
2012-07
影响因子：
4.2
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Ding S;Shi J;Qian W;Iqbal K;Grundke-Iqbal I;Gong CX;Liu F
作为选择性剪接的结果，成人大脑表达六种tau蛋白亚型。外显子10(E10)的选择性剪接导致tau亚型包含三个(3R)或四个(4R)微管结合重复序列。3R-tau/4R-tau比例失衡会导致神经纤维变性和痴呆。在这里，我们证明了双特异性酪氨酸磷酸化调节的激酶1A(Dyrk1A)与剪接因子9G8相互作用，并在几个丝氨酸残基上将其磷酸化。Dyrk1A本身促进tau E10包涵体，而9G8抑制E10包涵体，这些作用因细胞类型而异。Dyrk1A和9G8的共表达导致它们从细胞核移位到细胞质，并抑制了它们调节tau外显子10剪接的能力。这一作用可能是由于它们的相互作用诱导了从调控tau E10剪接的细胞核到细胞质的移位。这些发现对tau E10剪接调控的分子机制提供了新的见解，并进一步加深了我们对tau E10剪接失调引起的神经退行性变的理解。
Adult human brain expresses six isoforms of tau protein as a result of alternative splicing. Alternative splicing of exon 10 (E10) leads to tau isoforms containing either three (3R) or four (4R) microtubule-binding repeats. Imbalance in the 3R-tau/4R-tau ratio causes neurofibrillary degeneration and dementia. Here, we demonstrated that the dual-specificity tyrosine phosphorylation–regulated kinase 1A (Dyrk1A) interacted with the splicing factor 9G8 and phosphorylated it at several serine residues. Dyrk1A itself promoted tau E10 inclusion, whereas 9G8 inhibited E10 inclusion, and these actions were variable depending on the cell types. Co-expression of Dyrk1A and 9G8 led to their translocation from the nucleus to the cytoplasm and suppressed their ability to regulate tau exon 10 splicing. This action is probably due to their interaction-induced translocation from the nucleus, where the regulation of tau E10 splicing occurs, to the cytoplasm. These findings provide novel insights into the molecular mechanism of the regulation of tau E10 splicing and further our understanding of the neurodegeneration caused by dysregulation of tau E10 splicing.
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影响因子：
4.8
作者：
Liu, Fei;Liang, Zhihou;Gong, Cheng-Xin
通讯作者：
Gong, Cheng-Xin
影响因子：
4.7
作者：
Gao, QS;Memmott, J;Andreadis, A
通讯作者：
Andreadis, A
影响因子：
16.2
作者：
Ishihara, T;Hong, M;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
14.5
作者：
Stanford, PM;Shepherd, CE;Schofield, PR
通讯作者：
Schofield, PR