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
N1 - 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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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 -