Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes.
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.
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Therapeutics for Intractable Neurological Disorders, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan. Electronic address: ishigaki-ns@umin.net.
Shinsuke
S
Ishigaki
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Yusuke
Y
Fujioka
Department of Neurology, Aichi Medical University, School of Medicine, Aichi 480-1195, Japan.
Yohei
Y
Okada
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi 480-1195, Japan.
Yuichi
Y
Riku
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Tsuyoshi
T
Udagawa
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Daiyu
D
Honda
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Satoshi
S
Yokoi
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Kuniyuki
K
Endo
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Kensuke
K
Ikenaka
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Shinnosuke
S
Takagi
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Yohei
Y
Iguchi
Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Naruhiko
N
Sahara
Faculty of Science, Gakushuin University, Toshima-ku, Tokyo 171-8588, Japan.
Akihiko
A
Takashima
Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Hideyuki
H
Okano
Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi 480-1195, Japan.
Mari
M
Yoshida
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
Hitoshi
H
Warita
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
Masashi
M
Aoki
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Brain and Mind Research Center, Nagoya University, Nagoya, Aichi 466-8550, Japan.
Hirohisa
H
Watanabe
Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
Haruo
H
Okado
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Masahisa
M
Katsuno
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Brain and Mind Research Center, Nagoya University, Nagoya, Aichi 466-8550, Japan; Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan. Electronic address: sobueg@med.nagoya-u.ac.jp.
Gen
G
Sobue
D017398:Alternative Splicing / Q000502:physiology; D000818:Animals; D005091:Exons / Q000502:physiology; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D000072670:PTB-Associated Splicing Factor / Q000378:metabolism*; D010641:Phenotype; D020033:Protein Isoforms / Q000378:metabolism*; D012326:RNA Splicing / Q000502:physiology; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D000072670:PTB-Associated Splicing Factor; D020033:Protein Isoforms; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; D016875:tau Proteins
FTLD; FUS; SFPQ; adult neurogenesis; tau