Cyclic AMP-dependent protein kinase regulates the alternative splicing of tau exon 10: a mechanism involved in tau pathology of Alzheimer disease |
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Authors: | Shi Jianhua Qian Wei Yin Xiaomin Iqbal Khalid Grundke-Iqbal Inge Gu Xiaosong Ding Fei Gong Cheng-Xin Liu Fei |
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Affiliation: | Jiangsu Key Laboratory of Neuroregeneration, Medical School, Nantong University, Nantong, Jiangsu 226001, China. |
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Abstract: | 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. |
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Keywords: | Alzheimer Disease Neurodegeneration Protein Kinase A (PKA) RNA Splicing Tau Neurofibrillary Degeneration Serine/Arginine-rich Splicing Factor 1 |
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