Glycosphingolipid patterns and glycohydrolases behavior in acid-sphingomyelinase knock-out mice

Niemann-Pick type A (NPA) disease is a lysosomal storage disorder caused by a deficiency in the enzyme acid sphingomyelinase (ASMase). This inherited sphingolipidosis is characterized by a rapidly progressive neurodegenerative course. It is now known that secondary to sphingomyelin storage, other lipids, including gangliosides, also accumulate in NPA patients, leading to many cellular abnormalities. In particular we found that the lipid composition of different central nervous system and extraneural tissues from the acid sphingomyelinase-deficient mouse (ASMKO), the animal model for Niemann-Pick disease type A, is characterized by an unexpected, tissue specific selection of the accumulated molecular species of sphingomyelin, and an accumulation of GM3 and GM2 gangliosides in both neural and extraneural tissues, that cannot be solely explained by the lack of acid sphingomyelinase. On these bases, we determine the glycohydrolytic enzyme panel in ASMKO mice as experimental model. The activity of different glycohydrolases was measured in the homogenates of brain, cerebellum, liver, spleen and testis from male mice at 1.5, 3 and 6 months. In particular, b-glucosidase GBA1, GBA2, b-galactosidase, b-hexosaminidase and Neu3 sialidase were evaluated. The data obtained revealed that the activity of most of the enzymes increased with the age in the majority of the organs analyzed in both wild type and ASMKO mice. b-glucosidase GBA1 and b-hexosaminidase activities were significantly higher in ASMKO animals than in control mice. Remarkably, such increase in the activity of both the enzymes was already detectable at the first age considered. In addition, an increase in the activity of b-galactosidase and Neu3 was also detectable in ASKMO mice at 6 months when compared to wild type animals of the same age. These results suggest that the activity of several glycohydrolases is markedly altered in ASMKO mice, suggesting a possible role for some of these enzymes as earlier markers of NPA disease. In particular, GBA1 seems to represent a good candidate to be exploited for diagnostic and/or prognostic purposes