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- CLINICA NEUROL, 41: 1072－1074, 2001
- Vol.41 No.12 contents
The 42nd Annual Meeting of the Japanese Society of Neurology
Symposium II-4: Apoptosis of neurodegenerative disorders
The ubiquitin-proteasome system and neurodegeneration
Keiji Wada, M. D. , Hitoshi Osaka, M. D. , Syunsuke Aoki, Ph. D. and Yu-Lai Wang, M. D.
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry
Many studies have suggested the ubiquitin-proteasome system played an essential role in the pathogenesis of neurodegenerative disorders. In 1999, we provided evidence that a mutation of the system could directly cause neurodegeneration using the gad mouse. Namely, we identified the gad mutation was caused by an intragenic deletion of a gene encoding ubiquitin C-terminal hydrolase 1 (UCH-L1), which is a member of de-ubiquitinating enzyme family. In human, missense mutation of UCH-L1 gene was reported in a German family with Parkinson' s disease. As well, the parkin gene product was revealed to be an E3 ubiquitin ligase which recognize a form of α -synuclein as a substrate. Thus, the investigation of the ubiquitin-proteasome system should provide a clue for understanding neurodegeneration. We have characterized UCH-L1 and identified candidates of endogenous substrates as well as interacting proteins of UCH-L1. In addition, we found amount of monomeric ubiquitin was decreased in the brain of the gad mouse compared with wild type mice. We have also tried to develop "protein therapy" using UCH-L1 protein with TAT sequence. We observed the protein was delivered to brain after intraperitoneal injection in the wild type mouse. This approach would provide a new therapeutic strategy for neurodegeneration.
(CLINICA NEUROL, 41: 1072－1074, 2001)
key words: ubiquitin, neurodegenerative disorders, proteolysis, de-ubiquitinating enzyme, gad mouse
(Received: 12-May-01)
