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 Katsuno; Gen Sobue

doi:10.1016/j.celrep.2017.01.013

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 Katsuno

Gen Sobue

Research output: Contribution to journal › Article › peer-review

88 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 language	English
Pages (from-to)	1118-1131
Number of pages	14
Journal	Cell Reports
Volume	18
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2017.01.013
Publication status	Published - 31-01-2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2017.01.013

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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

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

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.",

keywords = "FTLD, FUS, SFPQ, adult neurogenesis, tau",

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

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s)",

year = "2017",

month = jan,

day = "31",

doi = "10.1016/j.celrep.2017.01.013",

language = "English",

volume = "18",

pages = "1118--1131",

journal = "Cell Reports",

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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, Katsuno, M & Sobue, G 2017, 'Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes', Cell Reports, vol. 18, no. 5, pp. 1118-1131. https://doi.org/10.1016/j.celrep.2017.01.013

TY - JOUR

T1 - Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes

AU - Ishigaki, Shinsuke

AU - Fujioka, Yusuke

AU - Okada, Yohei

AU - Riku, Yuichi

AU - Udagawa, Tsuyoshi

AU - Honda, Daiyu

AU - Yokoi, Satoshi

AU - Endo, Kuniyuki

AU - Ikenaka, Kensuke

AU - Takagi, Shinnosuke

AU - Iguchi, Yohei

AU - Sahara, Naruhiko

AU - Takashima, Akihiko

AU - Okano, Hideyuki

AU - Yoshida, Mari

AU - Warita, Hitoshi

AU - Aoki, Masashi

AU - Watanabe, Hirohisa

AU - Okado, Haruo

AU - Katsuno, Masahisa

AU - Sobue, Gen

PY - 2017/1/31

Y1 - 2017/1/31

N2 - 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.

AB - 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.

KW - FTLD

KW - FUS

KW - SFPQ

KW - adult neurogenesis

KW - tau

UR - https://www.scopus.com/pages/publications/85011659822

UR - https://www.scopus.com/pages/publications/85011659822#tab=citedBy

U2 - 10.1016/j.celrep.2017.01.013

DO - 10.1016/j.celrep.2017.01.013

M3 - Article

C2 - 28147269

AN - SCOPUS:85011659822

SN - 2211-1247

VL - 18

SP - 1118

EP - 1131

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -

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

Abstract

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