| Budget Amount *help |
¥48,620,000 (Direct Cost: ¥37,400,000、Indirect Cost: ¥11,220,000)
Fiscal Year 2010: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
Fiscal Year 2009: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
Fiscal Year 2008: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
Fiscal Year 2007: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
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| Research Abstract |
In this study, we analyzed the effect of genetic (I93M mutation) and environmental modification (oxidative stress) of a deubiquitinating enzyme, UCH-L1. In the brain, UCH-L1 shows neuron-specific expression and is believed to be involved in the pathogenesis of Parkinson's disease. We found that oxidized UCH-L1 showed its increased insolubility, and the formation of aggregation. These features were also observed in I93M IUCH-L1. Both oxidized UCH-L1 and I93M UCH-L1 showed the increased interaction with other proteins, and some of the proteins were overlapped. These findings suggest that oxidized UCH-L1 and I93M UCH-L1 share some molecular features. We next observed that gad mice, which lack the expression of UCH-L1, showed the deterioration of motor discoordination when they were fed with vitamin E-deficient diet. Wild type mice did not show any changes in motor function when they were fed with the diet. These observations suggest that UCH-L1 may play a protective role against oxidative stress in vivo, because vitamin E deficiency is know to cause the increase of oxidative stress in vivo. Then, we analyzed UCH-L3 null mutant. UCH-L3 is a homologue of UCH-L1 and shows ubiquitous expression in vivo. We observed that, in the mutant, lipid metabolism was altered in the muscle and adipose tissue. We also detected that monoubiquitin and di-ubiquitin are endogenous regulator of the enzyme activities of UCH-L1 and UCH-L3. These results suggests that the two enzymes co-operatively work in vivo.
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