Cyclic AMP-dependent Protein Kinase Regulates the Alternative Splicing of Tau Exon 10
Cyclic AMP-dependent Protein Kinase Regulates the Alternative Splicing of Tau Exon 10
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DOI：
10.1074/jbc.m110.204453
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发表时间：
2011-03
期刊：
影响因子：
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通讯作者：
Jianhua Shi;Wei Qian;Xiaomin Yin;K. Iqbal;I. Grundke‐Iqbal;X. Gu;F. Ding;C. Gong;Fei Liu
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文献类型：
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作者：
Jianhua Shi;Wei Qian;Xiaomin Yin;K. Iqbal;I. Grundke‐Iqbal;X. Gu;F. Ding;C. Gong;Fei Liu
过度磷酸化和tau沉积成神经原纤维缠结是阿尔茨海默病（AD）的一个标志。tau外显子10的选择性剪接产生含有3或4个微管结合重复序列（3R-tau和4R-tau）的tau同工型，它们在成人大脑中表达相同。外显子10的失调导致神经原纤维变性。在这里，我们报道了环amp依赖性蛋白激酶，PKA，磷酸化剪接因子SRSF1，调节其与tau前mrna的结合，并促进tau外显子10在培养细胞和大鼠脑中的包裹。PKA-Cα，而不是PKA-Cβ，与SRSF1相互作用并提高SRSF1介导的tau外显子10包合。在AD大脑中，PKA-Cα水平的降低与3R-tau水平的升高相关。这些发现表明，PKA的下调失调了tau外显子10的选择性剪接，并通过引起3R-tau和4R-tau表达的不平衡而导致AD的神经原纤维变性。
Hyperphosphorylation and deposition of tau into neurofibrillary tangles is a hallmark of Alzheimer disease (AD). Alternative splicing of tau exon 10 generates tau isoforms containing three or four microtubule binding repeats (3R-tau and 4R-tau), which are equally expressed in adult human brain. Dysregulation of exon 10 causes neurofibrillary degeneration. Here, we report that cyclic AMP-dependent protein kinase, PKA, phosphorylates splicing factor SRSF1, modulates its binding to tau pre-mRNA, and promotes tau exon 10 inclusion in cultured cells and in vivo in rat brain. PKA-Cα, but not PKA-Cβ, interacts with SRSF1 and elevates SRSF1-mediated tau exon 10 inclusion. In AD brain, the decreased level of PKA-Cα correlates with the increased level of 3R-tau. These findings suggest that a down-regulation of PKA dysregulates the alternative splicing of tau exon 10 and contributes to neurofibrillary degeneration in AD by causing an imbalance in 3R-tau and 4R-tau expression.