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2003 Fiscal Year Final Research Report Summary

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
Keywordsubiquitin / neurodegeneration / mouse / protein degradation / neuron / neurotransmission / neuroregeneration / synapse
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.

  • Research Products

    (8 results)

All Other

All Publications (8 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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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

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Published: 2005-04-19  

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