Osaka Hitoshi, Wang Yu-Lai, Takada Koji, Takizawa Shuichi, Setsuie Rieko, Li Hang, Sato Yae, Nishikawa Kaori, Sun Ying-Jie, Sakurai Mikako, Harada Takayuki, Hara Yoko, Kimura Ichiro, Chiba Shigeru, Namikawa Kazuhiko, Kiyama Hiroshi, Noda Mami, Aoki Shunsuke, Wada Keiji
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan.
Hum Mol Genet. 2003 Aug 15;12(16):1945-58. doi: 10.1093/hmg/ddg211.
Mammalian neuronal cells abundantly express a deubiquitylating enzyme, ubiquitin carboxy-terminal hydrolase 1 (UCH L1). Mutations in UCH L1 are linked to Parkinson's disease as well as gracile axonal dystrophy (gad) in mice. In contrast to the UCH L3 isozyme that is universally expressed in all tissues, UCH L1 is expressed exclusively in neurons and testis/ovary. We found that UCH L1 associates and colocalizes with monoubiquitin and elongates ubiquitin half-life. The gad mouse, in which the function of UCH L1 is lost, exhibited a reduced level of monoubiquitin in neurons. In contrast, overexpression of UCH L1 caused an increase in the level of ubiquitin in both cultured cells and mice. These data suggest that UCH L1, with avidity and affinity for ubiquitin, insures ubiquitin stability within neurons. This study is the first to show the function of UCH L1 in vivo.
哺乳动物神经元细胞大量表达一种去泛素化酶，即泛素羧基末端水解酶1（UCH L1）。UCH L1的突变与帕金森病以及小鼠的薄束轴索性营养不良（gad）有关。与在所有组织中普遍表达的UCH L3同工酶不同，UCH L1仅在神经元和睾丸/卵巢中表达。我们发现UCH L1与单泛素结合并共定位，延长了泛素的半衰期。在UCH L1功能丧失的gad小鼠中，神经元中的单泛素水平降低。相反，UCH L1的过表达导致培养细胞和小鼠中泛素水平升高。这些数据表明，对泛素有亲和力的UCH L1确保了神经元内泛素的稳定性。这项研究首次展示了UCH L1在体内的功能。
