| Project/Area Number |
16300126
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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 Institute of Neuroscience, National Center of Neurology and Psychiatry |
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Principal Investigator |
WADA Keiji National Institute of Neuroscience, Department of Degenerative Neurological Diseases, Director, 神経研究所疾病研究第四部, 部長 (70250222)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2006: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2005: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2004: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | ubiquitin / deubiquitinating enzyme / mouse / protein degradation / neuron / neurotransmission / neuroregeneration / synapse / parkin / 神経細胞死 / ALS / パーキンソン病 / 受容体 / オートファジー / 網膜 / アポトーシス / ミトコンドリア / 酸化ストレス / 酵素 / 神経発生 |
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| Research Abstract |
We previously identified that ubiquitin C-terminal hydrolase Ll (UCH-L1) is the responsible gene product for the gracile axonal dystrophy (gad) phenotype (Nature Genetics, 1999). UCH-L1 is a member of the deubiquitinating enzyme family and is selectively expressed in neurons. The gad mouse that lacks the expression of UCH-L1 is pathologically characterized by dying-back type of axonal degeneration. In this study, we aimed to elucidate the mechanism of a possible dynamic regulation of the maintenance and function of neural cells by deubiquitinating enzymes. We initially showed that UCH-L1 unexpectedly binds to and stabilizes monoubiquitin in neurons. This novel activity of UCH-L1 is independent on its hydrolase activity. We subsequently identified that this novel activity of UCH-Li is involved in the regulation of the activity of P2X type of ATP receptors and the morphology of neural progenitor cells. We further identified that UCH-L3, a related molecule to UCH-L1, is involved in cell apoptosis. In the retina of UCH-L3-deficient mice, caspase-independent apoptosis increased when retinal cells were insulted. UCH-L3 may have an opposing role against UCH-L1 in the cell apoptosis. In summary, we indicate that deubiquitinating enzymes may exert their biological activities in multiple ways
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