Establishment of a system for monitoring endoplasmic reticulum redox state in mammalian cells

2013 Fiscal Year Final Research Report

• Project/Area Number: 24659429
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: ISHIGAKI Shinsuke 名古屋大学, 医学(系)研究科(研究院), 助教 (40378170)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: ER stress / 神経変性疾患 / ALS / 小胞体ストレス

Research Abstract

The endoplasmic reticulum (ER) performs a critical role in the oxidative folding of nascent proteins such that perturbations to ER homeostasis may lead to protein misfolding and subsequent pathological processes. Among the mechanisms for maintaining ER homeostasis is a redox regulation, which is a critical determinant of the fate of ER stressed cells. Here we report the establishment of a system for monitoring ER redox state in mammalian cells. The new ER redox sensing system was developed based on the previously described monitoring system in yeast. Our system could successfully monitor the dynamic ER redox state in mammalian cells. Using this system, we find that manipulation of ER oxidases changes ER redox state. The mammalian ER redox sensing system could be used to study the mechanisms of ER redox regulation and provide a foundation for an approach to develop novel therapeutic modalities for human diseases related to dysregulated ER homeostasis including neurodegeneration.

Research Products

• [Journal Article] Lower Motor Neuron Involvement in TAR DNA-Binding Protein of 43 kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (2014)
  • Author(s): Riku Y, Watanabe H, Yoshida M, Tatsumi S, Mimuro M, Iwasaki Y, Katsuno M, Iguchi Y, Masuda M, Senda J, Ishigaki S, Udagawa T, Sobue G.
  • Journal Title: JAMA Neurol Volume: 71(2) Pages: 172-9
  • DOI: 10.1001/jamaneurol.2013.5489
• [Journal Article] The ALS/FTLD-related RNA-binding proteins TDP-43 and FUS have common downstream RNA targets in cortical neurons (2013)
  • Author(s): Honda D, Ishigaki S, Iguchi Y, Fujioka Y, Udagawa T, Masuda A, Ohno K, Katsuno M, Sobue G.
  • Journal Title: FEBS Open Bio Volume: 7 Pages: 1-10
  • DOI: 10.1016/j.fob.2013.11.001
• [Journal Article] Establishment of a system for monitoring endoplasmic reticulum redox state in mammalian cells (2013)
  • Author(s): Kanekura K, Ishigaki S, Merksamer P, Papa F, Urano F.
  • Journal Title: Lab Invest Volume: 93(11) Pages: 1254-8
  • DOI: 10.1038/labinvest.2013.112
• [Journal Article] FUS-regulated region- and cell-type-specific transcriptome is associated with cell selectivity in ALS/ FTLD (2013)
  • Author(s): Fujioka Y, Ishigaki S, Masuda A, Iguchi Y, Udagawa T, Watanabe H, Katsuno M, Ohno K, Sobue G.
  • Journal Title: Sci. Rep Volume: 3 Pages: 2388
  • DOI: 10.1038/srep02388
• [Journal Article] Thioredoxin-interacting protein mediates ER stress-inducedβcell death through initiation of the inflammasome (2012)
  • Author(s): Oslowski CM, Hara T, O'Sullivan-Murphy B, Kanekura K, Lu S, Hara M, Ishigaki S, Zhu LJ, Hayashi E, Hui ST, Greiner D, Kaufman RJ, Bortell R, Urano F.
  • Journal Title: Cell Metab Volume: 16(2) Pages: 265-73
  • DOI: 10.1016/j.cmet.2012.07.005
• [Journal Article] Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions (2012)
  • Author(s): Ishigaki S, Masuda A, Fujioka Y, Iguchi Y, Katsuno M, Shibata A, Urano F, Sobue G, Ohno K.
  • Journal Title: Sci Rep Volume: 2 Pages: 529
  • DOI: 10.1038/srep00529
• [Presentation] FUS regulates alternative splicing patterns of Mapt by cooperating with PSF/SFPQ : a novel link between FUS and Tau in the pathogenesis of ALS and FTLD. RNA Metabolism in Neurological Disease (2013)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Tsuyoshi Udagawa, Daiyu Honda, Masahisa Katsuno, and Gen Sobue
  • Organizer: 8th Brain Research Conference
  • Place of Presentation: San Diego, CAアメリカ合衆国
  • Year and Date: 2013-11-17
• [Presentation] FUS regulates alternative splicing patterns of Mapt by cooperating with PSF/SFPQ in association with clinicopathological features of ALS/FTLD : a novel link between FUS and Tau in the pathogenesis of ALS and FTLD (2013)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Tsuyoshi Udagawa, Daiyu Honda, Masahisa Katsuno, and Gen Sobue
  • Organizer: The 43rd Society for Neuroscience annual meeting
  • Place of Presentation: San Diego, CAアメリカ合衆国
  • Year and Date: 2013-11-10
• [Presentation] Comparison of Fus-regulating gene expression and alternative splicing profiles among different cell lineages in the central nervous system (2012)
  • Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Akio Masuda, Yohei Iguchi, Masahisa Katsuno, Kinji Ohno, and Gen Sobue
  • Organizer: The 42nd Society for Neuroscience annual meeting
  • Place of Presentation: New Orleans, LAアメリカ合衆国
  • Year and Date: 2012-10-14