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
| Project/Area Number |
13480262
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | National Center of Neurology and Psychiatry (NCNP) |
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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)
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| 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)
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| Project Period (FY) |
2001 – 2003
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| Keywords | ubiquitin / neurodegeneration / mouse / protein degradation / neuron / neurotransmission / neuroregeneration / synapse |
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| 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.
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[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)
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「研究成果報告書概要(欧文)」より
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[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)
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「研究成果報告書概要(欧文)」より
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[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)
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「研究成果報告書概要(欧文)」より
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[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)
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「研究成果報告書概要(欧文)」より
