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Journal of Lipid Research, Vol. 46, 1103-1112, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

C18:3-GM1a induces apoptosis in Neuro2a cells: enzymatic remodeling of fatty acyl chains of glycosphingolipids

Tetsuto Nakagawa, Akio Morotomi, Motohiro Tani, Noriyuki Sueyoshi, Hironobu Komori and Makoto Ito¹

Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 6-10-1, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan

Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M400516-JLR200

¹ To whom correspondence should be addressed. e-mail: makotoi{at}agr.kyushu-u.ac.jp

GM1a [Galß1-3GalNAcß1-4(NeuAc2-3)Galß1-4Glcß1-1Cer] is known to support and protect neuronal functions. However, 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. 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.

Abbreviations: Cer, ceramide; CTB, cholera toxin B-subunit; DIM, detergent-insoluble membrane; ERK, extracellular signal-regulated kinase; ESI-LC-MS, electrospray ionization-liquid chromatography-mass spectrometry; GM1a, Galß1-3GalNAcß1-4(NeuAc2-3)Galß1-4Glcß1-1Cer; GSL, glycosphingolipid; MAPK, mitogen-activated protein kinase; NCAM, neural cell adhesion molecule; SAPK/JNK, stress-activated protein kinase/c-Jun N-terminal kinase; SCDase, sphingolipid ceramide N-deacylase

Supplementary key words ganglioside • polyunsaturated fatty acids • neuroblastoma • lipid microdomain

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