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Molecluar mechanism of propagation of abnormal prion protein in the cells

Research Project

Project/Area Number 15208029
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied veterinary science
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

HORIUCHI Motohiro  Hokkaido University, Graduate School of Veterinary Medicine, Professor, 大学院・獣医学研究科, 教授 (30219216)

Co-Investigator(Kenkyū-buntansha) INABA Mutsumi  Hokkaido University, Graduate School of Veterinary Medicine, Professor, 大学院・獣医学研究科, 教授 (00183179)
OHASHI Kazuhiko  Hokkaido University, Graduate School of Veterinary Medicine, Associate Professor, 大学院・獣医学研究科, 助教授 (90250498)
MAEDA Akihiko  Hokkaido University, Graduate School of Veterinary Medicine, Associate Professor, 大学院・獣医学研究科, 助教授 (70333359)
FURUOKA Hidefumi  Obihiro University of Agriculture and Veterinary Medicine, Associate Professor, 畜産学部, 助教授 (60238665)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥35,490,000 (Direct Cost: ¥27,300,000、Indirect Cost: ¥8,190,000)
Fiscal Year 2005: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Fiscal Year 2004: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Fiscal Year 2003: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
Keywordsprion / scrapie / BSE / DNA Microarray / siRNA / Opti-MEM / Neuro2a
Research Abstract

In this research, we studied on the molecular mechanism of prion propagation in the cells through analyses of the effect of compounds that inhibit PrP^<Sc> formation and identification of host factor(s) and microenvironment that are involved in prion propagation.
Four different anti-PrP antibodies that react with PrP^C on the cell surface inhibited PrP^<Sc> formation in cells persistently infected with prion. The antibody-PrP^C complex on the cell surface was not internalized efficiently and tended to retain on the cell surface. These results suggest that anti-PrP mAb antagonized PrP^<Sc> formation by interfering with the regular PrP^C degradation pathway. In addition, we screened synthesized sulfated glycosides for the inhibition of PrP^<Sc> formation and found 4-sulfo-N-acetylglucosamie and 6-sulfo-N-acetylglucosamine inhibited PrPSc formation in prion-infected cells. These sulfated glycosides accelerated the endocytosis of PrP^C and reduced a total amount of PrP^C, while sulfated gly … More cosides that were not inhibited PrP^<Sc> formation did not reduce the total amount of PrP^C. These results indicated that sulfated glycosides and glycosaminoglycans inhibited PrP^<Sc> formation by facilitating the degradation of PrP^C.
We established subclones of Neuro2a (N2a) mouse neuroblastoma cells and distinguished prion-susceptible and non-susceptible subclones. One non-susceptible subclone, N2a-1, expressed PrP^C as the same level as parental N2a and other prion-susceptible subclones. There was no difference in the binding of PrP^<Sc> to the susceptible and non-susceptible subclones. Presence of N2a-1, which expresses PrP^C but is resistance to prion propagation, indicated the involvement of host factors other than PrP^C in prion propagation. To identify such host factors, the gene expression profiles between N2a subclones were analyzed by DNA microarray. We selected 36 and 18 genes, which expressed more than two-fold in prion susceptible subclone N2a-5 and prion resistant subclone N2a-1, respectively. We assessed the influence of these genes on prion susceptibility by reducing the gene expression by siRNA technique and found that siRNA against F2, Al, and C5 genes inhibited prion propagation in prion-infected N2a-5 cells. Less

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (53 results)

All 2006 2005 2004 2003 Other

All Journal Article (42 results) Book (1 results) Patent(Industrial Property Rights) (4 results) Publications (6 results)

  • [Journal Article] Alymphoplasia mice are resistant to prion infection via oral route.2006

    • Author(s)
      Horiuchi, M. et al.
    • Journal Title

      Jpn. J. Vet Med. 53

      Pages: 150-159

    • NAID

      120000953470

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Sequence variation of bovine prion protein gene in Japanese cattle (Holstein and Japanese Black).2006

    • Author(s)
      Nakamitsu, S. et al.
    • Journal Title

      J. Vet. Med. Sci. 68

      Pages: 27-33

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Distribution of PrP^<Sc> in cattle with bovine spongiform encephalopathy slaughtered at abattoirs in Japan.2006

    • Author(s)
      Iwata, N. et al.
    • Journal Title

      Jpn. J. Infect. Dis. 59

      Pages: 100-107

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Alymphoplasia mice are resistant to prion infection via oral route.2006

    • Author(s)
      Horiuchi, M. et al.
    • Journal Title

      Jpn.J.Vet Med. 53

      Pages: 150-159

    • NAID

      120000953470

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Sequence variation of bovine prion protein gene in Japanese cattle (Holstein and Japanese Black).2006

    • Author(s)
      Nakamitsu, S. et al.
    • Journal Title

      J.Vet.Med.Sci. 68

      Pages: 27-33

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Distribution of PrP^<Sc> in cattle with bovine spongiform encephalopathy slaughtered at abattoirs in Japan.2006

    • Author(s)
      Iwata, N. et al.
    • Journal Title

      Jpn.J.Infect.Dis. 59

      Pages: 100-107

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Alymphoplasia mice are resistant to prion infection via oral route.2006

    • Author(s)
      Horiuchi, M.et al.
    • Journal Title

      Jpn.J.Vet Med. 53

      Pages: 150-159

    • NAID

      120000953470

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Effective antigen-retrieval method for immunohistochemical detection of abnormal isoform of prion proteins in animals.2005

    • Author(s)
      Furuoka, H. et al.
    • Journal Title

      Acta Neuropathol. 109

      Pages: 263-271

    • NAID

      120006390093

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Surveillance of chronic wasting disease in sika deer, Cervus nippon, from Tokachi district in Hokkaido.2005

    • Author(s)
      Kataoka, N.et al.
    • Journal Title

      J. Vet. Med. Sci. 67

      Pages: 349-351

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Polymorphisms of caprine PrP gene detected in Japan.2005

    • Author(s)
      Kurosaki, Y.et al.
    • Journal Title

      J. Vet. Med. Sci. 67

      Pages: 321-323

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Conformational change in full-length mouse prion : A site-directed spin-labeling study.2005

    • Author(s)
      Inanami, O.et al.
    • Journal Title

      Biochem Biophys Res Commun 335

      Pages: 785-792

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 異常型プリオン蛋白質の生合成と伝達2005

    • Author(s)
      堀内 基広
    • Journal Title

      膜 30

      Pages: 78-83

    • NAID

      10015578051

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] BSE診断法の開発と現状2005

    • Author(s)
      堀内 基広
    • Journal Title

      Virus Report 2

      Pages: 20-27

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 人獣共通感染症としてのプリオン病2005

    • Author(s)
      堀内 基広
    • Journal Title

      ウイルス 55

      Pages: 45-55

    • NAID

      10016449383

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 動物由来感染症としてのプリオン病2005

    • Author(s)
      堀内 基広
    • Journal Title

      日本臨床 63

      Pages: 2213-2220

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Surveillance of chronic wasting disease in sika deer, Cervus nippon, from Tokachi district in Hokkaido.2005

    • Author(s)
      Kataoka, N. et al.
    • Journal Title

      J.Vet.Med.Sci. 67

      Pages: 349-351

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Polymorphisms of caprine PrP gene detected in Japan.2005

    • Author(s)
      Kurosaki, Y. et al.
    • Journal Title

      J.Vet.Med.Sci. 67

      Pages: 321-323

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Conformational change in full-length mouse prion : A site-directed spin-labeling study.2005

    • Author(s)
      Inanami, O. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun 335

      Pages: 785-792

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Biosynthesis and transmission of abnormal prion protein.2005

    • Author(s)
      Horiuchi, M.
    • Journal Title

      Membrane 30

      Pages: 78-83

    • NAID

      10015578051

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Development of BSE diagnosis methods and its current situation.2005

    • Author(s)
      Horiuchi, M.
    • Journal Title

      Virus Report 2

      Pages: 20-27

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Prion diseases as zoonisis.2005

    • Author(s)
      Horiuchi, M.
    • Journal Title

      Virus 55

      Pages: 45-55

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Prion diseases as infectous disease transmissible from animals to humas.2005

    • Author(s)
      Horiuchi, M.
    • Journal Title

      Jpn.J.Clin.Med. 63

      Pages: 2213-2220

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effective antigen-retrieval method for immunohistochemical detection of abnormal isoform of prion proteins in animals.2005

    • Author(s)
      Furuoka, H.et al.
    • Journal Title

      Acta Neuropathol 109

      Pages: 263-271

    • NAID

      120006390093

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Surveillance of chronic wasting disease in sika deer, Cervus nippon, from Tokachi district in Hokkaido.2005

    • Author(s)
      Kataoka, N.et al.
    • Journal Title

      J Vet Med Sci 67

      Pages: 349-351

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Polymorphisms of caprine PrP gene detected in Japan.2005

    • Author(s)
      Kurosaki, Y.et al.
    • Journal Title

      J Vet Med Sci 67

      Pages: 321-323

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 異常型プリオン蛋白質の生合成と伝達(Biosynthesis and transmission of abnormal prion protein)2005

    • Author(s)
      堀内 基広
    • Journal Title

      膜(membrane) 30

      Pages: 78-83

    • Related Report
      2005 Annual Research Report
  • [Journal Article] BSE診断法の開発と現状(Development of BSE diagnosis methods and its current situation)2005

    • Author(s)
      堀内 基広
    • Journal Title

      Virus Report 2

      Pages: 20-27

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Effective antigen-retrieval method for immunohistochemical detection of abnormal isoform of prion proteins in animals.2005

    • Author(s)
      Furuoka, H., et al.
    • Journal Title

      Acta Neuropathol (in press)

    • NAID

      120006390093

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Antigenic characterization of an abnormal isoform of prionprotein using a new diverse panel of monoclonal antibodies.2004

    • Author(s)
      Kim, C-L. et al.
    • Journal Title

      Virology 320

      Pages: 41-52

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cell surface retention of PrP^c by anti-PrP antibody prevents protease-resistant PrP formation.2004

    • Author(s)
      Kim, C-L. et al.
    • Journal Title

      J. Gen. Virol. 85

      Pages: 3473-3482

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Antigenic characterization of an abnormal isoform of prion protein using a new diverse panel of monoclonal antibodies.2004

    • Author(s)
      Kim, C-L. et al.
    • Journal Title

      Virology 320

      Pages: 41-52

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cell surface retention of PrP^c by anti-PrP antibody prevents protease-resistant PrP formation.2004

    • Author(s)
      Kim, C-L. et al.
    • Journal Title

      J.Gen.Virol. 85

      Pages: 3473-3482

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Antigenic characterization of an abnormal isoform of prion protein using a new diverse panel of monoclonal antibodies.2004

    • Author(s)
      Kim, C-L., et al.
    • Journal Title

      Virology 320

      Pages: 40-51

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cell surface retention of PrP^C by anti-PrP antibody prevents protease-resistant PrP formation.2004

    • Author(s)
      Kim, C.-L., et al.
    • Journal Title

      J.Gen.Virol. 85

      Pages: 3473-3482

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Unique amino acid polymorphisms of PrP genes in Mongolian sheep breeds.2004

    • Author(s)
      Gombojav, A., et al.
    • Journal Title

      J.Vet.Med.Sci 60

      Pages: 1923-1925

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cellular prion protein promotes Brucella Infection into macrophages.2003

    • Author(s)
      Watarai, M. et al.
    • Journal Title

      J. Exp. Med. 198

      Pages: 5-17

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Experimental Transmission of Abnormal Prion Protein (PrPsc) in the Small Intestinal Epithelial Cells of Neonatal Mice.2003

    • Author(s)
      Okamoto, M. et al.
    • Journal Title

      Vet Pathol. 40

      Pages: 723-727

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 抗PrP抗体によるプリオン増殖抑制とプリオン病治療の可能性2003

    • Author(s)
      堀内 基広
    • Journal Title

      最新医学 58

      Pages: 2802-2808

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 牛海綿状脳症問題に関する最近の動向2003

    • Author(s)
      堀内 基広
    • Journal Title

      老年精神医学雑誌 14

      Pages: 1488-1494

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cellular prion protein promotes Brucella Infection into macrophages.2003

    • Author(s)
      Watarai, M. et al.
    • Journal Title

      J.Exp.Med. 198

      Pages: 5-17

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibition of prion propagation by anti-PrP antibody and possible application for therapeutics.2003

    • Author(s)
      Horiuchi, M.
    • Journal Title

      The Medical Frontline 58

      Pages: 2802-2808

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Recent topic on bovine spongiform encephalopathy.2003

    • Author(s)
      Horiuchi, M.
    • Journal Title

      Jpn.J.Geriat.Psychi. 14

      Pages: 1488-1494

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 「スクレイピー」人と動物のプリオン病(山内一也, 立石潤監修)2003

    • Author(s)
      品川 森一, 堀内 基広
    • Total Pages
      47
    • Publisher
      近代出版
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] ヒトプリオン病を処置するための組成物2006

    • Inventor(s)
      堀内基広他
    • Industrial Property Rights Holder
      国立大学法人北海道大学他
    • Industrial Property Number
      2006-082037
    • Filing Date
      2006-03-24
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] プリオン増殖抑制剤2004

    • Inventor(s)
      鵜沢浩隆他
    • Industrial Property Rights Holder
      独立行政法人産業技術総合研究所他
    • Industrial Property Number
      2004-039121
    • Filing Date
      2004-02-17
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] プリオン病治療剤およびその製造方法2004

    • Inventor(s)
      藤永恵他
    • Industrial Property Rights Holder
      株式会社レノメッディクス研究所
    • Industrial Property Number
      2004-100649
    • Filing Date
      2004-03-30
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] 蛍光相関分光法による抗体の迅速検出及び/又は測定法2004

    • Inventor(s)
      金城政孝他
    • Industrial Property Rights Holder
      独立行政法人科学技術振興機構他
    • Industrial Property Number
      2004-166440
    • Filing Date
      2004-06-03
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] Watarai, M. et al.: "Cellular prion protein promotes Brucella Infection into macrophages"J.Exp.Med.. 198. 5-17 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Gombojav, A. et al.: "Susceptibility of Transgenic Mice Expressing Chimeric Sheep, Bovine and Human PrP Genes to Sheep Scrapie"J.Vet.Med.Sci.. 65. 341-347 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Okamoto, M. et al.: "Experimental Transmission of Abnormal Prion Protein (PrPsc) in the Small Intestinal Epithelial Cells of Neonatal Mice"Vet Pathol.. 40. 723-727 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kim, C-L. et al.: "Antigenic characterization of an abnormal isoform of prion protein using a new diverse panel of monoclonal antibodies"Virology. 320. 40-51 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 堀内 基広: "坑PrP抗体によるプリオン増殖抑制とプリオン病治療の可能性"最新医学. 58. 2802-2808 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 堀内 基広: "牛海綿状脳症問題に関する最近の動向"老人精神医学. 14. 1488-1494 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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