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DYNAMIC REGULATION OF THE MAINTENANCE AND FUNCTION OF NEURAL CELLS BY THE UBIOUITIN SYSTEM

泛素系统对神经细胞维持和功能的动态调节

基本信息

批准号：
16300126
负责人：
WADA Keiji
金额：
$ 9.47万
依托单位：
National Institute of Neuroscience, National Center of Neurology and Psychiatry
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

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

我们先前发现泛素C末端水解酶L1(UCH-L1)是细小轴突营养不良(GAD)表型的主要基因产物(自然遗传学，1999)。UCH-L1是脱泛素酶家族的一员，在神经元中选择性表达。缺乏UCH-L1表达的Gad小鼠的病理特征是消死型轴突变性。在这项研究中，我们旨在阐明脱泛素酶可能对神经细胞的维持和功能进行动态调节的机制。我们最初发现UCH-L1出人意料地与神经元中的Monoubiquitin结合并稳定。UCH-L1的这种新活性不依赖于其水解酶活性。我们随后发现，UCH-LI的这种新活性参与了对P2X型ATP受体活性和神经前体细胞形态的调节。我们进一步鉴定了UCH-L3，一个与UCH-L1相关的分子，参与了细胞凋亡。在UCH-L3缺陷小鼠的视网膜中，当视网膜细胞受到损伤时，caspase非依赖性的细胞凋亡增加。在细胞凋亡中，UCH-L3可能与UCH-L1具有相反的作用。综上所述，我们指出去泛素化酶可以通过多种方式发挥其生物学活性。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Potentiation of ATP‐induced currents due to the activation of P2X receptors by ubiquitin carboxy‐terminal hydrolase L1

DOI：
10.1111/j.1471-4159.2004.02963.x
发表时间：
2005-03
期刊：
Journal of Neurochemistry
影响因子：
4.7
作者：
Yoshimasa Manago;Yoshiko Kanahori;Aki Shimada;Ayumi Sato;Taiju Amano;Yae Sato-Sano;Rieko Setsuie;Mikako Sakurai;S. Aoki;Yu-Lai Wang;H. Osaka;K. Wada;M. Noda
通讯作者：
Yoshimasa Manago;Yoshiko Kanahori;Aki Shimada;Ayumi Sato;Taiju Amano;Yae Sato-Sano;Rieko Setsuie;Mikako Sakurai;S. Aoki;Yu-Lai Wang;H. Osaka;K. Wada;M. Noda

Accumulation of β- and γ-synucleins in the ubiquitin C-terminal hydrolase L1 deficient gad mouse.

泛素 C 末端水解酶 L1 缺陷的 gad 小鼠中 β- 和 γ-突触核蛋白的积累。