Journal Article Altered tau isoform ratio caused by loss of FUS and SFPQ function leads to FTLD-like phenotypes

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

18 ( 5 )  , pp.1118 - 1131 , 2017-01 , Cell Press
ISSN:2211-1247
Description
Fused in sarcoma (FUS) and splicing factor, prolineandglutamine-rich (SFPQ) are RNA binding proteinsthat regulate RNA metabolism. We found that alternativesplicing of the Mapt gene at exon 10, whichgenerates 4-repeat tau (4R-T) and 3-repeat tau(3R-T), is regulated by interactions between FUSand SFPQ in the nuclei of neurons. HippocampusspecificFUS- or SFPQ-knockdown mice exhibitfrontotemporal lobar degeneration (FTLD)-like behaviors,reduced adult neurogenesis, accumulationof phosphorylated tau, and hippocampal atrophywith neuronal loss through an increased 4R-T/3R-Tratio. Normalization of this increased ratio by 4R-Tspecificsilencing results in recovery of the normalphenotype. These findings suggest a biological linkamong FUS/SFPQ, tau isoform alteration, andphenotypic expression, which may function in theearly pathomechanism of FTLD.

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