Regulation of neuronal cell function organized by deubiquitinating enzymes

去泛素化酶组织的神经细胞功能的调节

基本信息

批准号：
19200032
负责人：
WADA Keiji
金额：
$ 31.12万
依托单位：
National Center of Neurology and Psychiatry
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2010
项目状态：
已结题

项目摘要

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.

在这项研究中，我们分析了去泛素化酶UCH-L1的遗传（I93M突变）和环境修饰（氧化应激）的影响。在大脑中，UCH-L1显示神经元特异性表达，被认为与帕金森氏病的发病机理有关。我们发现氧化的UCH-L1表现出其不溶性的增加，并形成了聚集。在I93M IUCH-L1中也观察到了这些功能。氧化的UCH-L1和I93M UCH-L1均显示出与其他蛋白质的相互作用增加，并且某些蛋白质被重叠。这些发现表明，氧化的UCH-L1和I93M UCH-L1具有一些分子特征。接下来，我们观察到缺乏UCH-L1表达的GAD小鼠在运动饮食中喂食运动时表现出恶化。野生型小鼠用饮食喂食运动功能没有任何变化。这些观察结果表明，UCH-L1可能对体内的氧化应激发挥保护作用，因为知道维生素E缺乏会导致体内氧化应激的增加。然后，我们分析了UCH-L3空突变体。 UCH-L3是UCH-L1的同源物，在体内显示无处不在的表达。我们观察到，在突变体中，脂质代谢在肌肉和脂肪组织中发生了改变。我们还检测到单纤维素和二泛素是UCH-L1和UCH-L3的酶活性的内源性调节剂。这些结果表明，这两种酶在体内合作起作用。

项目成果

期刊论文数量（69）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

virtual screeningによるUCH-Lファミリー活性調節剤探索研究

通过虚拟筛选寻找 UCH-L 家族活性调节剂的研究

DOI：
发表时间：
2007
期刊：
影响因子：
0
作者：
Hideki Kawahara;Masanori Morise;Torn Takahashi;Ryuichi Nisimura;Hideki Banno;Toshio Irino;平山和徳,青木俊介,西川香里,松本隆,和田圭司
通讯作者：
平山和徳,青木俊介,西川香里,松本隆,和田圭司

Aberrant interaction between familial Parkinson's disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy

家族性帕金森病相关突变体 UCH-L1 与伴侣介导的自噬溶酶体受体之间的异常相互作用