[The ubiquitin-proteasome system and neurodegeneration]

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 alpha-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.