Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases

Shinsuke Ishigaki, Yuichi Riku, Yusuke Fujioka, Kuniyuki Endo, Nobuyuki Iwade, Kaori Kawai, Minaka Ishibashi, Satoshi Yokoi, Masahisa Katsuno, Hirohisa Watanabe, Keiko Mori, Akio Akagi, Osamu Yokota, Seishi Terada, Ito Kawakami, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Mari Yoshida, Gen Sobue

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer's disease, or Pick's disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/ FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer's disease or Pick's disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/ 3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

Original languageEnglish
Pages (from-to)2398-2405
Number of pages8
Issue number8
Publication statusPublished - 01-08-2020

All Science Journal Classification (ASJC) codes

  • Clinical Neurology


Dive into the research topics of 'Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases'. Together they form a unique fingerprint.

Cite this