Cyclic AMP-Dependent Protein Kinase Enhances SC35-Promoted Tau Exon 10 Inclusion

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• 作者：Caoyi Chen (1) (2) (4)
  Nana Jin (2) (3)
  Wei Qian (2)
  Wen Liu (1)
  Xiangling Tan (4)
  Fei Ding (2)
  Xiaosong Gu (2)
  Khalid Iqbal (3)
  Cheng-Xin Gong (2) (3)
  Ji Zuo (1)
  Fei Liu (2) (3)
  
• 关键词：Alzheimer’s disease ; Tau ; Alternative splicing ; Cyclic AMP ; dependent protein kinase ; SC35
• 刊名：Molecular Neurobiology
• 出版年：2014
• 出版时间：February 2014
• 年：2014
• 卷：49
• 期：1
• 页码：615-624
• 全文大小：717 KB
• 作者单位：Caoyi Chen (1) (2) (4)
  Nana Jin (2) (3)
  Wei Qian (2)
  Wen Liu (1)
  Xiangling Tan (4)
  Fei Ding (2)
  Xiaosong Gu (2)
  Khalid Iqbal (3)
  Cheng-Xin Gong (2) (3)
  Ji Zuo (1)
  Fei Liu (2) (3)
  
  1. Department of Cellular and Genetic Medicine, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
  2. Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China
  4. Life Science Institute, Nantong University, Nantong, Jiangsu, 226019, People’s Republic of China
  3. Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY, 10314, USA
  
• ISSN：1559-1182

文摘

Alternative splicing of tau exon 10 generates tau with three or four microtubule-binding repeats (3R-tau or 4R-tau). The ratio of 3R-tau to 4R-tau is approximately 1:1 in the adult normal human brain. Disturbances in the ratio result in neurodegenerative tauopathies. Splicing factor SC35 acts on a SC35-like element located at the 5-end of tau exon 10 and promotes tau exon 10 inclusion. Here, we report that protein kinase (PKA) was able to interact and phosphorylate SC35. Activation or overexpression of PKA catalytic subunits promoted SC35-mediated tau exon 10 inclusion. Four PKA catalytic subunits, α1, α2, β1, and β2, all enhanced SC35-promoted tau exon 10 inclusion. SC35 has four putative PKA phosphorylation sites, Ser121, Ser128, Ser130, and Ser171. Pseudophosphorylation (SC354E) and blockage (SC354A) of phosphorylation of SC35 at these four sites increased and decreased, respectively, SC35’s ability to promote tau exon 10 inclusion. Moreover, PKA catalytic subunits no longer further enhanced tau exon 10 inclusion when these four were mutated to either alanine or glutamate. These results suggest that PKA interacts with and phosphorylates SC35 and enhances SC35-promoted tau exon 10 inclusion. In Alzheimer’s brain, down-regulation of the PKA pathway could lead to dysregulation of tau exon 10, contributing to tau pathogenesis.