ELUCIDATION OF THE MAINTENANCE MECHANISM OF SYNAPTIC STRUCTURE AND FUNCTION BY THE PROTEIN QUALTY CONTROL SYSTEM AND ITS APPLICATION TO NEUROREGENERATION

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We previously identified that ubiquitin C-terminal hydrolase L1 (UCH-L1) was not expressed in the gracile axonal dystrophy (gad) mouse. The gad mouse is pathologically characterized by dying-back type of axonal degeneration, and thus the mutant appears to be a suitable model for investigating the relationship between the ubiquitin system and synapes. In this study, we aimed to elucidate the physiological and pathophysiological roles of UCH-L1 in the maintenance of synaptic structure and function. We first identified that UCH-L1 unexpectedly bound to and stabilized monoubiquitin in neurons. In the stablization, hydrolase activity of UCH-L1 was not required. In the gad mouse, monoubiquitin level was decreased. These results suggest that UCH-L1 may function in multiple ways : as a hydrolase and as a ubiquitin-binding protein in vivo. Second, by proteaome analysis, we observed that four proteins were highly oxidized in the gad mouse. We also demonstrated that UCH-L1 itself was oxidized and decreased its hydrolase activity as the oxidation increased. Third, we observed that UCH-L1 played some role in synaptic plasticity. Since UCH-L1 is selectively expressed in neurons, our results suggest that UCH-L1 may play an essential role in synaptic transmission.