Secondary accumulations of gangliosides in sphingolipidosis

Sphingolipid metabolism is deeply deregulated in several pathologies. This seems to be responsible of neurodegeneration, in sphingolipidosis. Here, we focus the attention on secondary alterations of sphingolipid metabolism that have been sporadically reported in the literature, in some sphingolipidosis. We present a detailed analysis of the lipid composition in different tissues from the acid sphingomyelinase-deficient mouse (ASMKO), the animal model for Niemann-Pick disease type A, characterized by the accumulation of sphingomyelin (SM). The animal model of NPD type A, was developed using gene targeting and embryo transfer techniques. Results show, together with a general accumulation of SM, an unexpected tissue specific selection of the accumulated molecular species of SM, and of GM3 and GM2 gangliosides, that cannot be solely explained by the lack of sphingomyelinase. We observed the preferential accumulation of SM molecular species with shorter acyl chains in the nervous system, but not in extraneural tissues. The unbalance toward C18/C16-fatty acid containing SM species was detectable as early as SM accumulation started, and monosialoganglioside accumulation followed immediately afterwards. These changes in sphingolipid patterns should thus represent the effect of secondary biochemical pathways altered as a consequence of a non-related primary cause. The mechanism underlying these changes still remains to be elucidated and is probably the result of changes in the expression and/or activity of more than one single enzyme, and/or of anomalies in the traffic of the substrate/product concentrations in multiple cellular compartments. Several pieces of evidence suggest that altered sphingolipid metabolism results in a non-physiological plasma membrane composition and organization, leading to altered plasma membrane-originated signalling pathways that could be relevant to the onset of cellular damage and of tissue pathology.