Prevention of Lysosomal Storage in Tay-Sachs Mice Treated with N -Butyldeoxynojirimycin

Abstract

The glycosphingolipid (GSL) lysosomal storage diseases result from the inheritance of defects in the genes encoding the enzymes required for catabolism of GSLs within lysosomes. A strategy for the treatment of these diseases, based on an inhibitor of GSL biosynthesisN-butyldeoxynojirimycin, was evaluated in a mouse model of Tay-Sachs disease. When Tay-Sachs mice were treated withN-butyldeoxynojirimycin, the accumulation of G_M2in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, limiting the biosynthesis of the substrate (G_M2) for the defective enzyme (β-hexosaminidase A) prevents GSL accumulation and the neuropathology associated with its lysosomal storage.