A BIOCHEMICAL AND ULTRASTRUCTURAL EVALUATION OF THE TYPE-2 GAUCHER MOUSE

Gaucher mice, created by targeted disruption of the glucocerebrosidase gene, are totally deficient in glucocerebrosidase and have a rapidly deteriorating clinical course analogous to the most severely affected type 2 human patients. An ultrastructural study of tissues from these mice revealed glucocerebroside accumulation in bone marrow, liver, spl een, and brain. This glycolipid had a characteristic elongated tubular structure and was contained in lysosomes, as demonstrated by colocali zation with both ingested carbon particles and cathepsin D. In the cen tral nervous system (CNS), glucocerebroside was diffusely stored in mi croglia cells and in brainstem and spinal cord neurons, but not in neu rons of the cerebellum or cerebral cortex. This rostral-caudal pattern of neuronal lipid storage in these Gaucher mice replicates the patter n seen in type 2 human Gaucher patients and clearly demonstrates that glycosphingolipid catabolism and/or accumulation varies within differe nt brain regions. Surprisingly, the cellular pathology of tissue from these Gaucher mice was relatively mild, and suggests that the early an d rapid demise of both Gaucher mice and severely affected type 2 human neonates may be the result of both a neurotoxic metabolite, such as g lucosylsphingosine, and other factors, such as skin water barrier dysf unction secondary to the absence of glucocerebrosidase activity.