Disialoganglioside GD3 is released by microglia and induces oligodendrocyte apoptosis.
Increased brain ganglioside levels are a hallmark of various neuroinflammatory pathologies. Here, we provide evidence that murine microglia can secrete disialoganglioside GD3 upon exposure to inflammatory stimuli. Comparison of different neural cell types revealed a particular and specific sensitivity of oligodendrocytes towards exogenous GD3. Oligodendrocyte death triggered by GD3 was preceded by degeneration of cellular processes, and associated with typical features of apoptosis, such as chromatin condensation, exposure of phosphatidylserine, release of cytochrome c from mitochondria, and loss of mitochondrial membrane potential, followed by the loss of plasma membrane integrity and detachment of disintegrated oligodendrocytes. Overexpression of bcl-2 partially protected oligodendrocytes from death. In contrast, treatment with the pan-caspase inhibitor zVAD-fmk did not prevent phosphatidylserine exposure, chromatin margination at the nuclear periphery, and death, although caspase-3 was blocked. Thus, GD3 produced by microglia under neuroinflammatory conditions may function as a novel mediator triggering mitochondria-mediated, but caspase-independent, apoptosis-like death of oligodendrocytes.
Simon
B M
BM
Department of Molecular Toxicology, University of Konstanz, 78457 Konstanz, Germany.
Malisan
F
F
Testi
R
R
Nicotera
P
P
Leist
M
M
D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology*; D010718:Phosphatidylserines / Q000378:metabolism
D061945:Caspase Inhibitors; D005732:Gangliosides; D010718:Phosphatidylserines; C025447:sialogangliosides; C026226:ganglioside, GD3