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Research on the pathophysiology and treatment of neurological disorders modified by nonsense-mediated mRNA decay (NMD)

Research Project

Project/Area Number 20591015
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionNational Institute for Minamata Disease

Principal Investigator

USUKI Fusako  National Institute for Minamata Disease, 臨床部, 室長 (50185013)

Co-Investigator(Kenkyū-buntansha) 山下 暁朗  横浜市立大学, 医学部・微生物学, 講師 (20405020)
樋口 逸郎  鹿児島大学, 医学部・老年神経内科, 准教授 (80183573)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsNonsense-mediated mRNA decay (NMD) / NMD構成分子 / siRNA, NMD抑制 / Ullrich病繊維芽細胞 / 腫瘍細胞 / 細胞生理機能 / 生体ストレス応答 / Nonsense-mediated mRNA decay(NMD) / siRNA / NMD抑制 / ノックダウン / HeLa細胞 / 細胞増殖 / SMG-8 / nonsense-mediated mRNA decay NMD / セレノシステイン / セレノプロテイン / グルタチオンペルオキシダーゼ1 / Upf1 / SMG-1 / SMG-7
Research Abstract

Nonsense-mediated mRNA decay (NMD), an mRNA quality surveillance mechanism, affects disease condition by modifying post-transcriptionally the expression of disease-related gene carrying premature termination codons (PTCs). Among them some disease conditions are recovered by NMD suppression, which up-regulates the mutant mRNA and restores partially the defect of protein and cellular function. Using Ullrich's disease fibroblasts as a model cell line of PTC-harbored genetic diseases exacerbated by NMD, we investigated effects of NMD suppression on cellular physiological functions. NMD suppression by siRNAs targeted to NMD components neither affects cellular cycle nor causes ER stress. However, knockdown of 6 NMD components except SMG-8 suppressed cell growth although the effects were much milder than those on epithelial carcinoma cell line (HeLa cells). In addition, we clarified that selenoenzymes were affected by NMD execution and oxidative stress was induced under selenium deficiency by exposure to a chemical toxin.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (21 results)

All 2011 2010 2009

All Journal Article (9 results) (of which Peer Reviewed: 6 results) Presentation (9 results) Book (3 results)

  • [Journal Article] Posttranscriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure.2011

    • Author(s)
      Usuki F, Yamashita A, Fujimura M
    • Journal Title

      J Biol Chem 286

      Pages: 6641-9

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methyl-mercury exposure.2011

    • Author(s)
      Fujimura M, Usuki F, Kawamura M, Izumo S
    • Journal Title

      Toxicol Appl Pharm 250

      Pages: 1-9

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure.2011

    • Author(s)
      Usuki F, Yamashita A, Fujimum M
    • Journal Title

      J Biol Chem

      Volume: 286 Pages: 6641-6649

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure.2011

    • Author(s)
      Fujimura M, Usuki F, Kawamura M, Izumo S
    • Journal Title

      Toxicol Appl Pharm

      Volume: 250 Pages: 1-9

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] NMDによる変異mRNA排除と疾患2010

    • Author(s)
      臼杵扶佐子、山下暁朗
    • Journal Title

      細胞工学 19

      Pages: 155-160

    • Related Report
      2010 Final Research Report
  • [Journal Article] Nonsense-mediated mRNA decay(NMD)による変異mRNA排除と疾患2010

    • Author(s)
      臼杵扶佐子、山下暁朗
    • Journal Title

      細胞工学 29

      Pages: 155-160

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of c-jun-N-terminal kinase pathway in the cerebral cortex, but not inthe hippocampus of the mouse brain.2009

    • Author(s)
      Fujimura M, Usuki F, Sawada M, Takashima A
    • Journal Title

      NeuroToxicology 30

      Pages: 1000-1007

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Methylmercury exposure down- regulates the expression of Rac l and leads to neuritic degeneration and ultimately apoptosis incerebrocortical neurons.2009

    • Author(s)
      Fujimura M, Usuki F, Sawada M, Rostene W, Godefroy D, Takashima, A
    • Journal Title

      NeuroToxicology 30

      Pages: 16-22

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] NMDによるmRNA排除と疾患…難治性遺伝性疾患治療への試み.2009

    • Author(s)
      山下暁朗、臼杵扶佐子
    • Journal Title

      蛋白質・核酸・酵素 増刊

      Pages: 2219-2225

    • Related Report
      2009 Annual Research Report
  • [Presentation] Posttranscriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure.2011

    • Author(s)
      Usuki F
    • Organizer
      NIMD FORUM 2011
    • Place of Presentation
      Minamata
    • Year and Date
      2011-01-26
    • Related Report
      2010 Annual Research Report
  • [Presentation] Posttranscriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure.2011

    • Author(s)
      臼杵扶佐子
    • Organizer
      NIMD FORUM 2011
    • Place of Presentation
      Minamata, Jan
    • Related Report
      2010 Final Research Report
  • [Presentation] Methylmercury causes oxidative stress through its posttranscriptional effect on antioxidant selenoenzymes.2010

    • Author(s)
      Usuki F, Yamashita A, Fujimura M
    • Organizer
      XVII^<th> International Congress of Neuropathology
    • Place of Presentation
      Austria, Salzburg
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain.2010

    • Author(s)
      Fujimura M, Usuki F, Takashima A
    • Organizer
      XVIIt^<th> International Congress of Neuropathology
    • Place of Presentation
      Austria, Salzburg
    • Related Report
      2010 Final Research Report
  • [Presentation] メチル水銀による酸化ストレス発生2010

    • Author(s)
      臼杵扶佐子
    • Organizer
      北陸大学サテライトミーティング
    • Place of Presentation
      水俣
    • Related Report
      2010 Final Research Report
  • [Presentation] Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mousebrain.2010

    • Author(s)
      Fujimura M, Usuki F, Takashima A
    • Organizer
      XVII^<th> International Congress of Neuropathology
    • Place of Presentation
      Austria, Salzburg
    • Related Report
      2010 Annual Research Report
  • [Presentation] メチル水銀による酸化ストレス発生2010

    • Author(s)
      臼杵扶佐子
    • Organizer
      北陸大学学術フロンティア・サテライトミーティング
    • Place of Presentation
      水俣
    • Related Report
      2009 Annual Research Report
  • [Presentation] Disease conditions associated with nonsense-mediated mRNA decay (NMD)2009

    • Author(s)
      臼杵扶佐子
    • Organizer
      第82回 日本薬理学会年会シンポジウム
    • Place of Presentation
      横浜
    • Year and Date
      2009-03-16
    • Related Report
      2008 Annual Research Report
  • [Presentation] Disease conditions associated with nonsense-mediated mRNA decay (NMD)シンポジウム「ナンセンス変異と疾患2009

    • Author(s)
      臼杵扶佐子
    • Organizer
      mRNAサーベイランス機構NMDを介した疾病発症のメカニズムと新規治療薬」第82回日本薬理学会年会
    • Place of Presentation
      横浜
    • Related Report
      2010 Final Research Report
  • [Book] mRNA監視機構の生命現象、疾患への寄与とその分子機構.実験医学増刊「拡大・進展を続けるRNA研究の最先端」(塩見春彦、塩見美喜子、稲田利文、廣瀬哲郎編集)2010

    • Author(s)
      山下暁朗、臼杵扶佐子
    • Publisher
      羊土社
    • Related Report
      2010 Final Research Report
  • [Book] 実験医学増刊「拡大・進展を続けるRNA研究の最先端」(塩見春彦、塩見美喜子、稲田利文、廣瀬哲郎編集)2010

    • Author(s)
      山下暁朗、臼杵扶佐子
    • Total Pages
      205
    • Publisher
      mRNA監視機構の生命現象、疾患への寄与とその分子機構
    • Related Report
      2010 Annual Research Report
  • [Book] NMDによるmRNA排除と疾患-----難治性遺伝性疾患治療への試み.蛋白質・核酸・酵素増刊mRNAプログラム 多様性と非対称性の獲得戦略(稲田利文、大野睦人編集)2009

    • Author(s)
      山下暁朗、臼杵扶佐子
    • Publisher
      共立出版, 東京
    • Related Report
      2010 Final Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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