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 - 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.
UR - http://www.scopus.com/inward/record.url?scp=85011659822&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011659822&partnerID=8YFLogxK
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 -