Ganglioside GM3 is involved in neuronal cell death.
Gangliosides abundant in the nervous system have been implicated in a broad range of biological functions, including the regulation of cell proliferation and death. Glutamate-induced cell death, which is accompanied by an accumulation of reactive oxygen species (ROS), is a major contributor to pathological cell death within the nervous system. However, the mechanism underlying this neuronal cell death has not been fully elucidated. In this study, we report that ganglioside GM3 is involved in neuronal cell death. GM3 was up-regulated in the mouse hippocampal cell line HT22 death caused by glutamate. Increment in GM3 levels by both the exogenous addition of GM3 and the overexpression of the GM3 synthase gene induced neuronal cell death. Overexpression of GM3 synthase by microinjecting mRNA into zebrafish embryos resulted in neuronal cell death in the central nervous system (CNS). Conversely, RNA interference-mediated silencing of GM3 synthase rescued glutamate-induced neuronal death, as evidenced by the inhibition of massive ROS production and intracellular calcium ion influx. 12-lipoxygenase (12-lipoxygenase) (12-LOX) was recruited to glycosphingolipid-enriched microdomains (GEM) in a GM3-dependent manner during oxidative glutamate toxicity. Our findings suggest that GM3 acts as not only a mediator of oxidative HT22 death by glutamate but also a modulator of in vivo neuronal cell death.
Sohn
Hosung
H
Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-333, Korea.
Kim
Yong-Sam
YS
Kim
Hyun-Taek
HT
Kim
Cheol-Hee
CH
Cho
Eun-Wie
EW
Kang
Hye-Yeon
HY
Kim
Nam-Soon
NS
Kim
Cheorl-Ho
CH
Ryu
Seong Eon
SE
Lee
Jeong-Hwa
JH
Ko
Jeong Heon
JH
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005679:G(M3) Ganglioside / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology; D021962:Membrane Microdomains / Q000201:enzymology; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D016415:Sequence Alignment; D012799:Sialyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D015027:Zebrafish / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D005679:G(M3) Ganglioside; D017382:Reactive Oxygen Species; D029961:Zebrafish Proteins; D018698:Glutamic Acid; D001092:Arachidonate 12-Lipoxygenase; D012799:Sialyltransferases; C021343:haematoside synthetase; D002118:Calcium