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Human Molecular Genetics Advance Access originally published online on July 1, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 16 1945-1958
DOI: 10.1093/hmg/ddg211
© 2003 Oxford University Press

Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron

Hitoshi Osaka1,2,{dagger},{ddagger}, Yu-Lai Wang1,{dagger}, Koji Takada3, Shuichi Takizawa1,4, Rieko Setsuie1,5, Hang Li1, Yae Sato1,5, Kaori Nishikawa1, Ying-Jie Sun1, Mikako Sakurai1,5, Takayuki Harada1, Yoko Hara1,6, Ichiro Kimura6, Shigeru Chiba4, Kazuhiko Namikawa7, Hiroshi Kiyama7, Mami Noda5, Shunsuke Aoki1 and Keiji Wada1,*

1Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan, 2Information and Cellular function, PRESTO, Japan Science and Technology Corporation (JST), Kawaguchi, Saitama 332-0012, Japan, 3Department of Biochemistry 1, Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan, 4Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa, 078-8510, Japan, 5Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka, 812-8582, Japan, 6Department of Basic Human Science, School of Human Science, Waseda University, Tokorozawa, 359-1192, Japan and 7Department of Anatomy and Neurobiology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, 545-8585, Japan

Received March 13, 2003; Revised June 6, 2003; Accepted June 17, 2003

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.

* To whom correspondence should be addressed at: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, 187-8502, Japan. Tel: +81 423461715; Fax: +81 423461745; Email: wada{at}ncnp.go.jp

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} Present address: Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, 232-8555, Japan.


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