Deficiency of ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) leads to vulnerability to lipid peroxidation

Lipid peroxidation has many deleterious effects on cells, and in the nervous system is considered to be involved in the pathogenesis of neurodegenerative diseases. To suppress lipid peroxidation, cells have various defense systems such as glutathione and thioredoxin, and defects in these defense systems will result in disturbance of normal cellular functions. Here we report that deficiency of ubiquitin carboxyterminal hydrolase-L1 (UCH-L1) leads to vulnerability to lipid peroxidation both in vivo and in vitro, through analyses of the UCH-L1-deficient mutant mouse gracile axonal dystrophy (gad). In the gracile fasciculus of gad mice, punctate deposits were observed to be immunoreactive for 4-hydroxy-2-nonenal, a by-product of lipid peroxidation. The motor deficits of gad mice were worsened by a diet deficient in vitamin E. When neurons from dorsal root ganglions (DRG) were cultured in the vitamin E-free medium, cell death was increased in the neurons of gad mice. These data suggest that UCH-L1 has a function in protecting DRG neurons from lipid peroxidation. Further, we describe newly identified properties: that UCH-L1 is localized on the inside of the plasma membrane of DRG neurons, and that UCH-L1 binds to phosphatidic acid according to the redox status and presence of mono-ubiquitin protein. These findings will provide clues for elucidating the physiological function of UCH-L1. (C) 2010 Elsevier Ltd. All rights reserved.