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ELUCIDATION OF THE MAINTENANCE MECHANISM OF SYNAPTIC STRUCTURE AND FUNCTION BY THE PROTEIN QUALTY CONTROL SYSTEM AND ITS APPLICATION TO NEUROREGENERATION

Research Project

Project/Area Number 13480262
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionNational Center of Neurology and Psychiatry (NCNP)

Principal Investigator

WADA Keiji  National Center of Neurology and Psychiatry, National Institute of Neuroscience, Department of Degenerative Neurological Diseases, Director, 疾病研究第四部, 部長 (70250222)

Co-Investigator(Kenkyū-buntansha) NODA Mami  Kyushu University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究院, 助教授 (80127985)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2001: ¥7,800,000 (Direct Cost: ¥7,800,000)
Keywordsubiquitin / neurodegeneration / mouse / protein degradation / neuron / neurotransmission / neuroregeneration / synapse / 幹細胞 / 神経軸索 / パーキンソン病 / 神経細胞死
Research Abstract

We previously identified that ubiquitin C-terminal hydrolase L1 (UCH-L1) was not expressed in the gracile axonal dystrophy (gad) mouse. The gad mouse is pathologically characterized by dying-back type of axonal degeneration, and thus the mutant appears to be a suitable model for investigating the relationship between the ubiquitin system and synapes. In this study, we aimed to elucidate the physiological and pathophysiological roles of UCH-L1 in the maintenance of synaptic structure and function. We first identified that UCH-L1 unexpectedly bound to and stabilized monoubiquitin in neurons. In the stablization, hydrolase activity of UCH-L1 was not required. In the gad mouse, monoubiquitin level was decreased. These results suggest that UCH-L1 may function in multiple ways : as a hydrolase and as a ubiquitin-binding protein in vivo. Second, by proteaome analysis, we observed that four proteins were highly oxidized in the gad mouse. We also demonstrated that UCH-L1 itself was oxidized and decreased its hydrolase activity as the oxidation increased. Third, we observed that UCH-L1 played some role in synaptic plasticity. Since UCH-L1 is selectively expressed in neurons, our results suggest that UCH-L1 may play an essential role in synaptic transmission.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Harada, T.et al.: "Role of ubiquitin carboxy terminal hydrolase-L1 in neural cell --"Am.J.Pathol.. 164・1. 59-64 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Castegna, A.at al.: "Proteomic analysis of brain proteins in the gracile axonal dystrophy (gad) mouse, --"Neurochem.. 88・6. 1540-1546 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Osaka, H.at al.: "Ubiquitin carboxy-terminal hydrolase L1 binds to ---"Hum.Mol.Genet.. 12・16. 1945-1958 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nishikawa, K.et al.: "Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin"Biochem.Biophys.Res.Comm.. 304・1. 176-183 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nishikawa, K., Li, H., Kawamura, R., Osaka, H., Wang, Y.L., Hara, Y., Hirokawa, T., Manago, Y., Amano, T, Noda, M., Aoki, S., Wada, K.: "Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants."BBRC. 304. 176-183 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Osaka, H., Wang, Y.L., Takada, K., Takizawa, S., Setsuie, R., Li, H., Sato, Y., Nishikawa, K., Sun, Y.J., Sakurai, M., Harada, T., Hara, Y., Kimura, I., Chiba, S., Namikawa, K., Kiyama, H., Noda, M., Aoki, S., Wada, K.: "Ubiquitin. carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neurons."Hum.Mol.Genet.. 12. 1945-1958 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Castegna, A., Thongboonkerd, V., Klein, J., Lynn, B., Wang, Y.L., Osaka, H., Wada, K., Butterfield, D.A.: "Proteomic analysis of brain proteins in the gracile axonal dystrophy (gad) mouse, a syndrome that emanates from dysfunctional ubiquitin carboxyl-terminal hydrolase L-1,reveals oxidation of key proteins."J.Neurochem.. 88. 1540-1546 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harada, T., Harada, C., Wang, Y.L., Osaka, H., Amanai, K., Tanaka, K., Takizawa, K., Setsuie, R., Sakurai, M., Sato, Y., Noda, M., Wada, K.: "Role of ubiquitin carboxy terminal hydrolase-LI in neural cell apoptosis induced by ischemic retinal injury in vivo."Am.J.Pathol.. 164. 59-64 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Costegna, A. et al.: "Proteomic Analysis of the Brain Proteins in the Gracile Axonal --"J.Neurochem.. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishikawa, K et al.: "Alterations of structure and hydrolase activity of parkinsonism-associated --"Biochem.Biophys.Res.Comm.. 304. 176-183 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Aoki, S. et al.: "Identification of a novel axotomy-induced glycosylated protein, AIGP1, possibly involved in cellular apoptosis triggered by ER-Golgi stress"J. Neurosci.. 22. 10751-10760 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishikawa, K et al.: "Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants"Biochem. Biophys. Res. Comm.. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kurihara, L.J. et al.: "Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior--"Human Mol.Genet.. 10. 1963-1970 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Osawa, Y. et al.: "Cloning, expression, and mapping of a mouse gene, Uchl4, highly homologous--"Biochem.Biohys.Res.Comm.. 283. 627-623 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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