• Top page
  • Timetable
  • Per session
  • Per presentation
  • How to
  • Meeting Planner



ポリグルタミン病、ALS、脊髄小脳変性症、その他の神経変性疾患 1
Polyglutamine Diseases, ALS, SCD, Other Neurodegenerative Disorder 1

開催日 2014/9/11
時間 9:00 - 10:00
会場 Room I(311+312)
Chairperson(s) 秦野 伸二 / Shinji Hadano (東海大学医学部基礎医学系分子生命科学 / Department of Molecular Life Sciences, Tokai University School of Medicine, Japan)
小野寺 理 / Osamu Onodera (新潟大学脳研究所 / Brain Research Institute, Niigata University, Japan)

Quality loss of FUS and SFPQ in the nucleus causes FTLD-like behavioral abnormalities by modulating Tau isoforms

  • O1-I-1-3
  • 石垣 診祐 / Shinsuke Ishigaki:1 藤岡 祐介 / Yusuke Fujioka:1 宇田川 剛 / Tsuyoshi Udagawa:1 本田 大祐 / Daiyu Honda:1 横井 聡 / Satoshi Yokoi:1 勝野 雅央 / Masahisa Katsuno:1 岡戸 春生 / Haruo Okado:2 祖父江 元 / Gen Sobue:1 
  • 1:名古屋大院・医・神経内科 / Department of Neurology, Nagoya University, Graduate School of Medicine, Japan 2:東京都医学総合研究所・神経細胞分化 / Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan 

FUS is genetically and clinicopathologically linked to amyotrophic sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We found that FUS made a high-molecular weight complex in the nucleus of neurons which was uncompleted in the ALS-associated mutants of FUS. A splicing factor, proline- and glutamine-rich (SFPQ) was identified as a component of the high-molecular complex of FUS. Disease-associated mutations of FUS deteriorated the interaction with SFPQ in the nucleus of neurons. Pathological specimen analysis showed that there was a decrease of intranuclear co-localization of FUS and SFPQ in neurons at motor cortex and hippocampus of both familial and sporadic ALS/FTLD. Interestingly, both FUS and SFPQ regulate alternative splicing of Mapt gene at exon10 which generates two pathogenic isoforms of Tau protein, three-repeat Tau (RD3) and four-repeat Tau (RD4). Defect of FUS or SFPQ result in the increased ratio of RD4/RD3 in neurons. Wild-type FUS overexpression can reverse the skipping of exon10 of Mapt caused by FUS-silencing but disease-associated mutants cannot. The ratio of RD4/RD3 was increased in the frontal cortex of ALS/FTLD patients in which the interaction between FUS and SFPQ was weaken. Morphological abnormality of neurite was observed in FUS-silenced primary neurons and it was rescued by overexpression of wild-type FUS but not by mutant FUS. This aberrant morphology was also recovered by silencing of RD4. Silencing of FUS in adult mice hippocampus by injecting AAV encoding shRNA against FUS or SFPQ exhibited increased ratio of RD4/RD3 in hippocampus. Abnormal anxiety behaviors were observed in hippocampal FUS or SFPQ knock-down mice which mimicked FTLD-like behavioral impairments. These phenotypes were rescued by co-silencing of RD4 in hippocampus. Thus, our findings suggest a pathophysiological link between FUS and Tau via SFPQ in ALS/FTLD through the regulation of RD4/RD3 isoforms.

Copyright © Neuroscience2014. All Right Reserved.