Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes

Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Yuichi Riku, Tsuyoshi Udagawa, Daiyu Honda, Satoshi Yokoi, Kuniyuki Endo, Kensuke Ikenaka, Shinnosuke Takagi, Yohei Iguchi, Naruhiko Sahara, Akihiko Takashima, Hideyuki Okano, Mari Yoshida, Hitoshi Warita, Masashi Aoki, Hirohisa Watanabe, Haruo Okado, Masahisa KatsunoGen Sobue

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD.

Original languageEnglish
Pages (from-to)1118-1131
Number of pages14
JournalCell Reports
Volume18
Issue number5
DOIs
Publication statusPublished - 2017 Jan 31

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Keywords

  • adult neurogenesis
  • FTLD
  • FUS
  • SFPQ
  • tau

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ishigaki, S., Fujioka, Y., Okada, Y., Riku, Y., Udagawa, T., Honda, D., Yokoi, S., Endo, K., Ikenaka, K., Takagi, S., Iguchi, Y., Sahara, N., Takashima, A., Okano, H., Yoshida, M., Warita, H., Aoki, M., Watanabe, H., Okado, H., ... Sobue, G. (2017). Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes. Cell Reports, 18(5), 1118-1131. https://doi.org/10.1016/j.celrep.2017.01.013