Journal of Molecular Neuroscience

, 45:453

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

Authors

  • Payal Ray
    • Department of Neurology, Lurie Cancer Center, Center for Genetic MedicineNorthwestern University Feinberg School of Medicine
  • Amar Kar
    • Department of Neurology, Lurie Cancer Center, Center for Genetic MedicineNorthwestern University Feinberg School of Medicine
  • Kazuo Fushimi
    • Department of Neurology, Lurie Cancer Center, Center for Genetic MedicineNorthwestern University Feinberg School of Medicine
  • Necat Havlioglu
    • Department of PathologySaint Louis University
  • Xiaoping Chen
    • Department of Neurology, Lurie Cancer Center, Center for Genetic MedicineNorthwestern University Feinberg School of Medicine
    • Department of Neurology, Lurie Cancer Center, Center for Genetic MedicineNorthwestern University Feinberg School of Medicine
Article

DOI: 10.1007/s12031-011-9634-z

Cite this article as:
Ray, P., Kar, A., Fushimi, K. et al. J Mol Neurosci (2011) 45: 453. doi:10.1007/s12031-011-9634-z

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.

Keywords

Tau Alternative splicing regulation Tauopathy RNA stem-loop secondary structure Polypyrimidine tract binding protein associated splicing factor (PSF)

Copyright information

© Springer Science+Business Media, LLC 2011