Abstract
GM1a [Gal beta1-3GalNAc beta1-4(NeuAc alpha2-3)Gal beta1-4Glc beta1-1Cer] is known to support and protect neuronal functions. However, we report that alpha-linolenic acid-containing GM1a (C18:3-GM1a), which was prepared using the reverse hydrolysis reaction of sphingolipid ceramide N-deacylase, induced apoptosis in neuronal cells. Intranucleosomal DNA fragmentation, chromatin condensation, and caspase activation, all typical features of apoptosis, were observed when mouse neuroblastoma Neuro2a cells were cultured with C18:3-GM1a but not GM1a containing stearic acid (C18:0) or oleic acid (C18:1). The phenotype of Neuro2a cells induced by C18:3-GM1a was similar to that evoked by lyso-GM1a. However, lyso-GM1a caused a complete disruption of lipid microdomains of Neuro2a cells and hemolysis of sheep erythrocytes, whereas C18:3-GM1a did neither. C18:3-GM1a, but not lyso-GM1a, was found to be abundant in lipid microdomains after the removal of loosely bound GM1a by BSA. The activation of stress-activated protein kinase/c-Jun N-terminal kinase in Neuro2a cells was observed with lyso-GM1a but not C18:3-GM1a. These results indicate that the mechanism of apoptosis induced by C18:3-GM1a is distinct from that caused by lyso-GM1a. This study also clearly shows that fatty acid composition of gangliosides significantly affected their pharmacological activities when added to the cell cultures and suggests why naturally occurring gangliosides do not possess polyunsaturated fatty acids as a major constituent.
Highlights
GM1a [Gal1-3GalNAc1-4(NeuAc␣2-3)Gal14Glc1-1Cer] is known to support and protect neuronal functions
The present study indicates that remodeling of fatty acyl chains of GSLs is performed by sphingolipid ceramide N-deacylase (SCDase), an enzyme capable of catalyzing reversible reactions by which the N-acyl linkage of Cer in GSLs is hydrolyzed or synthesized [22, 23]
These results suggest that the length of fatty acyl chains is more important in determining the efficiency of the condensation reaction by the SCDase than is the degree of unsaturation of the fatty acid, if the reaction period is long enough with an excess amount of enzyme
Summary
GM1a [Gal1-3GalNAc1-4(NeuAc␣2-3)Gal14Glc1-1Cer] is known to support and protect neuronal functions. We report that ␣-linolenic acid-containing GM1a (C18:3-GM1a), which was prepared using the reverse hydrolysis reaction of sphingolipid ceramide N-deacylase, induced apoptosis in neuronal cells. The activation of stress-activated protein kinase/c-Jun N-terminal kinase in Neuro2a cells was observed with lyso-GM1a but not C18:3-GM1a. These results indicate that the mechanism of apoptosis induced by C18:3-GM1a is distinct from that caused by lyso-GM1a. Clinical applications of GM1a for neurological disorders such as Alzheimer’s disease [16], Parkinson’s disease [17], and spinal cord injury [18] have been reported These studies and clinical applications did not focus on the role of the ceramide (Cer) moiety of gangliosides in the activity.
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