The increased sensitivity of neurons with elevated glucocerebroside to neurotoxic agents can be reversed by imiglucerase

We have recently demonstrated that incubation of cultured rat hippocampal n eurons with conduritol beta-epoxide (CBE), an inhibitor of glucocerebrosida se, the enzyme defective in Gaucher disease, results in changes in intracel lular morphology and in functional calcium stores. Changes in levels of fun ctional calcium stores are directly related to neuronal cell death. We now show that neurons incubated with either CBE or a non-hydrolysable analogue of GlcCer (glucosylthioceramide), are more sensitive to the toxic effects o f high concentrations of glutamate and of a variety of metabolic inhibitors . A linear relationship exists between level of accumulation of GlcCer and the extent of neuronal cell death. The deleterious effects of elevated GlcC er levels can be completely reversed by addition of human glucocerebrosidas e (imiglucerase) to the culture medium. Imiglucerase is internalized to lys osomes, where it presumably degrades excess GlcCer. This suggests that the limited success of enzyme replacement therapy in neuronopathic forms of Gau cher disease is not due to lack of efficacy of glucocerebroside in degradin g GlcCer in neurons of the central nervous system, and adds impetus to atte mpts to develop ways to efficiently deliver glucocerebrosidase to the brain s of neurologically compromised Gaucher disease patients.