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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300126/
• 关键词: 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

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

我们先前识别出泛素C末端水解酶LL（UCH-L1）是Gracile轴突营养不良（GAD）表型的负责基因产物（Nature Genetics，1999）。 UCH-L1是去泛素化酶家族的成员，在神经元中有选择地表达。缺乏UCH-L1表达的GAD小鼠在病理上以轴突变性的垂死类型的形式表征。在这项研究中，我们旨在通过去泛素化酶来阐明神经细胞维持和功能的动态调节机制。我们最初表明，UCH-L1意外结合并稳定神经元中的单喹素。 UCH-L1的这种新活性在其水解酶活性上是独立的。随后，我们发现UCH-LI的这种新活性参与了P2X类型ATP受体的活性和神经祖细胞的形态的调节。我们进一步确定UCH-L3是与UCH-L1相关的分子，与细胞凋亡有关。在UCH-L3缺陷型小鼠的视网膜中，当视网膜细胞被侮辱时，与胱天蛋白酶无关的细胞凋亡增加。 UCH-L3在细胞凋亡中可能与UCH-L1具有相反的作用。总而言之，我们表明去泛素化酶可能以多种方式发挥其生物活性

项目成果

Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's -----

表达帕金森症的转基因小鼠中多巴胺能神经元损失 -----

• 发表时间: 2007
• 期刊: Neurochem. Int. 50・1
• 作者: Setsuie;R. et al.
• 通讯作者: R. et al.

Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant.

表达帕金森病相关 UCH-L1 I93M 突变体的转基因小鼠中多巴胺能神经元损失。

• 发表时间: 2007
• 期刊: Neurochem.Int. 50・1
• 作者: Setsuie;R. et al.
• 通讯作者: R. et al.

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。

• 发表时间: 2004
• 期刊: Brain Res. 1019・1-2
• 作者: Wang;Y.L.et al.
• 通讯作者: Y.L.et al.

Two closely related ubiquitin C-terminal hydrolase isozymes function as reciprocal modulators of germ cell apoptosis in cryptorchid testes.

两种密切相关的泛素 C 末端水解酶同工酶在隐睾睾丸中充当生殖细胞凋亡的相互调节剂。

• 发表时间: 2004
• 期刊: Am. J. Pathol. 165・4
• 作者: Kwon;J. et al.
• 通讯作者: J. et al.

The region-specific functions of two ubiquitin C-terminal hydrolase isozymes along the epididymis.

附睾中两种泛素 C 末端水解酶同工酶的区域特异性功能。

• 发表时间: 2006
• 期刊: Exp. Anim. 55・1
• 作者: Kwon;J. et al.
• 通讯作者: J. et al.