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

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Abstract

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.

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Acknowledgments

We thank Ms. J. Murphy for secretarial assistance. This work was supported in part by Nantong University and the New York State Office for People with Developmental Disabilities, and grants from the National Natural Science Foundation of China (81030059 and 30973143 to L.F.), the U.S. Alzheimer’s Association (IIRG-10-173154 to L.F.), the Basic Research Program of Jiangsu Education Department (10KJA310040 to L.F.), and the Priority Academic Program Development of Jiangsu Higher Education institutions (PAPD).

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Cellular and Genetic Medicine, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

    Caoyi Chen, Wen Liu & Ji Zuo

  2. Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China

    Caoyi Chen, Nana Jin, Wei Qian, Fei Ding, Xiaosong Gu, Cheng-Xin Gong & Fei Liu

  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

    Nana Jin, Khalid Iqbal, Cheng-Xin Gong & Fei Liu

  4. Life Science Institute, Nantong University, Nantong, Jiangsu, 226019, People’s Republic of China

    Caoyi Chen & Xiangling Tan

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  1. Caoyi Chen
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Chen, C., Jin, N., Qian, W. et al. Cyclic AMP-Dependent Protein Kinase Enhances SC35-Promoted Tau Exon 10 Inclusion. Mol Neurobiol 49, 615–624 (2014). https://doi.org/10.1007/s12035-013-8542-3

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  • DOI: https://doi.org/10.1007/s12035-013-8542-3

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