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 KatsunoGen Sobue

生理学

研究成果: Article › 査読

63 被引用数 (Scopus)

抄録

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.

本文言語	English
ページ（範囲）	1118-1131
ページ数	14
ジャーナル	Cell Reports
巻	18
号	5
DOI	https://doi.org/10.1016/j.celrep.2017.01.013
出版ステータス	Published - 2017 1月 31

ASJC Scopus subject areas

生化学、遺伝学、分子生物学（全般）

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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

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

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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 = "Funding Information: A part of this study represents the results of the “Integrated Research on Neuropsychiatric Disorders” and “Integrated Research on Depression, Dementia and Development Disorders” projects carried out under the Strategic Research Program for Brain Sciences and Brain/MINDS of the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Agency for Medical Research and Development. This work was also supported by Mext Grant-in-aid project, Scientific Research on Innovation Area (Brain Protein Aging and Dementia control), by Mext Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network), by Mext KAKENHI grant number 15K09310, and by CREST from JST. We thank K. Lipson, Y. Soeda, M. Shimojo, N. Suzuki, T. Akiyama, and T. Miyasaka for helpful discussions and A. Miwa and S. Hirai for technical support of AAV production. Publisher Copyright: {\textcopyright} 2017 The Author(s)",

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

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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

N1 - Funding Information: A part of this study represents the results of the “Integrated Research on Neuropsychiatric Disorders” and “Integrated Research on Depression, Dementia and Development Disorders” projects carried out under the Strategic Research Program for Brain Sciences and Brain/MINDS of the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Agency for Medical Research and Development. This work was also supported by Mext Grant-in-aid project, Scientific Research on Innovation Area (Brain Protein Aging and Dementia control), by Mext Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network), by Mext KAKENHI grant number 15K09310, and by CREST from JST. We thank K. Lipson, Y. Soeda, M. Shimojo, N. Suzuki, T. Akiyama, and T. Miyasaka for helpful discussions and A. Miwa and S. Hirai for technical support of AAV production. Publisher Copyright: © 2017 The Author(s)

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.

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KW - FUS

KW - SFPQ

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KW - tau

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AN - SCOPUS:85011659822

SN - 2211-1247

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EP - 1131

JO - Cell Reports

JF - Cell Reports

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

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