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PSF Suppresses Tau Exon 10 Inclusion by Interacting with a Stem-Loop Structure Downstream of Exon 10

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Abstract

Microtubule binding protein Tau has been implicated in a wide range of neurodegenerative disorders collectively classified as tauopathies. Exon 10 of the human tau gene, which codes for a microtubule binding repeat region, is alternatively spliced to form Tau protein isoforms containing either four or three microtubule binding repeats, Tau4R and Tau3R, respectively. The levels of different Tau splicing isoforms are fine-tuned by alternative splicing with the ratio of Tau4R/Tau3R maintained approximately at one in adult neurons. Mutations that disrupt tau exon 10 splicing regulation cause an imbalance of different tau splicing isoforms and have been associated with tauopathy. To search for factors interacting with tau pre-messenger RNA (pre-mRNA) and regulating tau exon 10 alternative splicing, we performed a yeast RNA–protein interaction screen and identified polypyrimidine tract binding protein associated splicing factor (PSF) as a candidate tau exon 10 splicing regulator. UV crosslinking experiments show that PSF binds to the stem-loop structure at the 5′ splice site downstream of tau exon 10. This PSF-interacting RNA element is distinct from known PSF binding sites previously identified in other genes. Overexpression of PSF promotes tau exon 10 exclusion, whereas down-regulation of the endogenous PSF facilitates exon 10 inclusion. Immunostaining shows that PSF is expressed in the human brain regions affected by tauopathy. Our data reveal a new player in tau exon 10 alternative splicing regulation and uncover a previously unknown mechanism of PSF in regulating tau pre-mRNA splicing.

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Acknowledgment

We are grateful for generous help from Dr. James Patton (Vanderbilt University) and Dr. Douglas Black (UCLA) for various reagents. We thank members of the Wu laboratory for helpful discussions, critical reading and suggestions. This work was supported by National Institutes of Health (R01 AG033004 and R56NS074763 to JYW).

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Authors and Affiliations

  1. Department of Neurology, Lurie Cancer Center, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Payal Ray, Amar Kar, Kazuo Fushimi, Xiaoping Chen & Jane Y. Wu

  2. Department of Pathology, Saint Louis University, St. Louis, MO, USA

    Necat Havlioglu

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  1. Payal Ray
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  2. Amar Kar
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  3. Kazuo Fushimi
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  4. Necat Havlioglu
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  5. Xiaoping Chen
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  6. Jane Y. Wu
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Correspondence to Jane Y. Wu.

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Ray, P., Kar, A., Fushimi, K. et al. PSF Suppresses Tau Exon 10 Inclusion by Interacting with a Stem-Loop Structure Downstream of Exon 10. J Mol Neurosci 45, 453–466 (2011). https://doi.org/10.1007/s12031-011-9634-z

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  • DOI: https://doi.org/10.1007/s12031-011-9634-z

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