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Proteasome regulates dopaminergic neuronel degeneration and Lewy body formation

Research Project

Project/Area Number14570591
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

SAWADA Hideyuki  KYOTO UNIVERSITY, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (30335260)

Co-Investigator(Kenkyū-buntansha) SHIMOHAMA Shun  KYOTO UNIVERSITY, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (60235687)
Project Period (FY) 2002 – 2003
Project Status Completed(Fiscal Year 2003)
Budget Amount *help
¥4,000,000 (Direct Cost : ¥4,000,000)
Fiscal Year 2003 : ¥1,600,000 (Direct Cost : ¥1,600,000)
Fiscal Year 2002 : ¥2,400,000 (Direct Cost : ¥2,400,000)
KeywordsParkinson's disease / α-synuclein / MPP^+ / rotenone / proteasome / Lewy body / dopamine / ミトコンドリア / ニューロン死 / ドーパミンニューロン / MPTP / MPP+
Research Abstract

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. α-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death have not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed and caspase-3 is activated in the affected midbrain. In this research project, we demonstrated that a combination of 1-methyl-4-phenylpyridinium ion (MPP^+) or rotenone and proteasome inhibition caused the appearance of α-synuclein positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP^+-or rotenone-induced dopaminergic neuronal death. MPP^+ elevated the activity of 26S proteasome, dephosphorylated mitogen activating kinase (MAPK) and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p-42 and p-44 MAPK kinase inhibitor. Thus the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.

Report

(3results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report

Research Products

(30results)

All Other

All Publications

  • [Publications] Sawada H, et al.: "Estradiol protects dopaminergic neurons in a MPP^+ Parkinson's disease model."Neuropharmacology. 42. 1056-1064 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kihara T, et al.: "Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade."J Neurosci Res. 70. 274-282 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Udaka F, et al.: "White matter lesions and dementia : MR1-pathological correlation"Ann.N.Y.Acad.Sci. 977. 411-415 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawada H, et al.: "Estrogens and Parkinson disease : novel approach for neuroprotection"Endocrine. 21. 77-79 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakamizo T, et al.: "Phosphodiesterase Inhibitors are neuroprotective to cultured spinal motor neurons"J.Neurosci.Res.. 71. 485-495 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimohama S, et al.: "Disease model : Parkinson's disease"Trends Mol.Med.. 9. 360-365 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakka N et al.: "Dopamine is involved in selectivity of dopaminergic neuronal death by roteuone."Neuroreport. 14. 2425-2428 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawada H. et al.: "Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-Synuclein inclusions"J.Biol.Chem. 279. 10710-10719 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kohno R. et al.: "BDNF is induced by wild-type α-synuclein but not by the two mutants, A30P or A53T, in glioma cell line."Biochem.Biophys.Res.Commun.. 318. 113-118 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanki R et al.: "Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons"Brain Res.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawada H, Ibi M, KiharaT, Honda K, Nakanishi M, Sakka N, Akaike A, Shimohama S.: "Estradiol protects dopaminergic neurons in a MPP^+ Parkinson's disease model."Neuropharm acology. 42. 1056-1064 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Kanki R, Yamashita H, Akaike A.: "Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidvlinositol 3 kinase cascade."J Neurosci Res.. 70. 274-282 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Udaka F, Sawada_H, Kameyama M.: "White matter lesions and dementia: MRI-pathological correlation."Ann.N.Y.Acad.Sci.. 977. 411-415 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawada H, Shimohama S.: "Estrogens and Parkinson disease: novel approach for neuroprotection."Endocrine. 21. 77-79 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakamizo T, Kawamata J, Yoshida K, Kawai Y, Kanki R, Sawada H, Kihara T, Yamashita H, Shibasaki H, Akaike A, Shimohama S.: "Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons."J.Neurosci Res.. 71. 485-495 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimohama S, Sawada H, Kitamura Y, Taniguchi T.: "Disease model: Parkinson's disease."Trends Mol Med.. 9. 360-365 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sakka N.Sawada H, Izumi Y, Kume T, Katsuki H, Kaneko S, Shimohama S, Akaike A.: "Dopamine is involved in selectivity of dopaminemic neuronal death by rotenone."Neuroreport. 14. 2425-2428 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawada H, Kohno R, Kihara T, Izumi Y, Sakka N, Ibi M, Nakanishi M, Nakamizo T, Yamakawa K, Shibasaki H, Yamamoto N, Akaike A, Inden M, Kitamura Y, Taniguchi T, Shimohama S.: "Proteasome mediates dopaminergic neuronal deaeneration, and its inhibition causes alpha-"J.Biol.Chem.. 279. 10710-10719 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kohno R, Sawada_H, Kawamoto Y, Uemura K, Shibasaki H, Shimohama S.: "BDNF is induced by wild-type alpha-synuclein but not by the two mutants, A3OP or A53T, in"Biochem.Biophys.Res.Commun.. 318. 113-118 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanki R, Kihara T, Nakamizo T, Kawamata J, Yamashita H, Sawada H, Shibasaki H, Akaike A, Shimohama S.: "Effects of m itochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons."Brain Res.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawada H: "Estradiol protects dopaminergic neurons in a MPP^+ Parkinson's disease model"Neuropharmacology. 42・8. 1056-1064 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kihara T: "Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade"Journal of Neuroscience Research. 70・3. 274-282 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sawada H: "Estrogens and Parkinson's Disease : Novel approach for neuroprotection"Endocrine. 21・1. 77-79 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimohama S: "Disease model : Parkinson's disease"Trends in Molecular Medicine. 9・8. 360-365 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sakka N: "Dopamine is involved in selectivity of dopaminergic neuronal death by rotenone"Neuroreport. 14・18. 2425-2428 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sawada H: "Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-synuclein inclusions"Journal of Biological Chemistry. 279・11. 10710-10719 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sawada H., et al.: "Estrogens and Parkinson's disease : Novel approach for neuroprotection"Endocrine. (発表予定).

    • Related Report
      2002 Annual Research Report
  • [Publications] Sawada H., et al.: "Estradiol protects dopaminergic neurons in a MPP + Parkinson's disease model"Neuropharmacology. 42・8. 1056-1064 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kihara T., et al.: "Protective effect of dopamine D_2 agonists in cortical neurons via the phosphaticlyl 3 kinase cascade"J. Neurosci. Res.. 70・3. 274-282 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamizo T., et al.: "Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons"J. Neurosci. Res.. 71・4. 485-495 (2003)

    • Related Report
      2002 Annual Research Report

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Published : 2002-04-01   Modified : 2016-04-21  

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