AGE-RELATED ACCUMULATION OF HIGH-MOLECULAR-WEIGHT UBIQUITIN PROTEIN CONJUGATES IN MOUSE BRAINS

It has been demonstrated that the amount of ubiquitin (Ub)-protein con jugates increases in tire whole brain homogenates of old mice. To dete rmine the specificity of the accumulation of the conjugates, we furthe r investigated age-related changes in Ub-protein conjugates in other t issues (heart, liver, and kidney), and also in various regions (cerebr um, cerebellum, brain stem, and medulla oblongata) of the brain. The a mount of high-molecular-weight Ub-protein conjugates (HMW > 60KDa) inc reased remarkably in all regions of the brain examined, especially in the cerebellum, of senescent mice, but not much in other tissues. No a ppreciable difference in the size of free Ub pool was found between yo ung and old mice except in the medulla oblongata. This suggests that t he increase in Ub-protein conjugates is not simply due to a rise in th e free Ub pool. The activity of isopeptidases in homogenates was estim ated by measuring rates of deubiquitination of endogenous Ub-protein c onjugates under ATP-depleted conditions. In the brain stern and medull a oblongata, they decreased significantly with age. In the cerebrum an d cerebellum, however, no significant difference was observed between young and old animals. These results partially explain the increases o bserved in medulla and brain stem, but cannot explain the increases in cerebrum and cerebellum.