Apoptosis and signalling in acid sphingomyelinase deficient cells

An alternative explanation is put forward whereby the accumulation of intracellular sphingomyelin in sphingomyelinase deficient cells leads to the formation of intracellular rafts which lead to the sequestration of important signalling molecules that are normally present on the cell surface where they perform their function.It is expected that the subcellular distribution of important signalling molecules is altered in acid sphingomyelinase deficient cells, leading to their sequestration in late endosomes / lysosomes. Other sphingolipid storage diseases such as Niemann-Pick type C which have normal acid sphingomyelinase activity would also be expected to show the same phenotype.If true the hypothesis would provide a mechanism for the pathology of the sphingolipid storage diseases at the cellular level and also have implications for the role of ceramide in apoptosis.Recently reported data shed further light on the interrelationships between caspase activation, the scrambling of membrane phospholipid asymmetry and the production of ceramide which can occur during apoptosis signalling. Firstly, since signalling by the caspase cascade can occur very rapidly elucidation of whether ceramide production or caspase activation comes first is of great importance. A large body of evidence now suggests that inhibition of inducer caspases such as FLICE also inhibit ceramide formation [1-3]. These observations suggest that ceramide generation is downstream of the early signalling events in apoptosis. Moreover, late generation of ceramide indicates that ceramide formation may be a consequence of the execution of apoptosis rather than a signal. During the execution of apoptosis the activation of a non-specific phospholipid membrane scramblase leads to the general disruption of phospholipid asymmetry, the externalisation of phosphatidylserine and membrane blebbing. Membrane blebbing and phosphatidyserine exposure signal a physiological endpoint since they lead to engulfment by profes