Creation of a mouse model for non-neurological (type B) Niemann-Pick disease by stable, low level expression of lysosomal sphingomyelinase in the absence of secretory sphingomyelinase: relationship between brain intra-lysosomal enzyme activity and central nervous system function

Most lysosomal storage diseases result in neurodegeneration, but deficienci es in the same enzymes can also lead to syndromes without neurologic manife stations, The hypothesis that low levels of residual, intra-lysosomal enzym atic activities in the central nervous system (CNS) are protective has been difficult to prove because of inconsistencies in assays of tissue samples. Experimental correction of lysosomal enzyme deficiencies in animal models suggests that low-level enzymatic activity may reduce CNS pathology, but th ese results are difficult to interpret owing to the partial and transient n ature of the improvements, the presence of secretory hydrolases, and other confounding factors. Using a novel transgenic/knockout strategy to manipula te the intracellular targeting of a hydrolase, we created a mouse that stab ly expresses low levels of lysosomal sphingomyelinase (L-SMase) in the comp lete absence of secretory sphingomyelinase (S-SMase), The brains of these m ice exhibited 11.5-18.2% of wild-type L-SMase activity, but the cerebellar Purkinje cell layer, which is lost by 4 months of age in mice completely la cking L- and S-SMase, was preserved for at least 8 months, The L-SMase acti vities in other organs were 1-14% of wild-type levels, and by 8 months of a ge all peripheral organs had accumulated sphingomyelin and demonstrated pat hological intracellular inclusions. Most importantly, L-SMase-expressing mi ce showed no signs of the severe neurologic disease observed in completely deficient mice, and their life span and general health were essentially nor mal, These findings show that stable, continuous, low-level expression of i ntra-lysosomal enzyme activity in the brain can preserve CNS function in th e absence of secretory enzyme or other confounding factors.