Glycogen synthase kinase-3/Shaggy mediates ethanol-induced excitotoxic cell death of Drosophila olfactory neurons.
It has long been known that heavy alcohol consumption leads to neuropathology and neuronal death. While the response of neurons to an ethanol insult is strongly influenced by genetic background, the underlying mechanisms are poorly understood. Here, we show that even a single intoxicating exposure to ethanol causes non-cell-autonomous apoptotic death specifically of Drosophila olfactory neurons, which is accompanied by a loss of a behavioral response to the smell of ethanol and a blackening of the third antennal segment. The Drosophila homolog of glycogen synthase kinase-3 (GSK-3)beta, Shaggy, is required for ethanol-induced apoptosis. Consistent with this requirement, the GSK-3beta inhibitor lithium protects against the neurotoxic effects of ethanol, indicating the possibility for pharmacological intervention in cases of alcohol-induced neurodegeneration. Ethanol-induced death of olfactory neurons requires both their neural activity and functional NMDA receptors. This system will allow the investigation of the genetic and molecular basis of ethanol-induced apoptosis in general and provide an understanding of the molecular role of GSK-3beta in programmed cell death.
French
Rachael L
RL
Department of Anatomy and Program in Neuroscience, University of California at San Francisco, 1550 4th Street, San Francisco, CA 94143-2324, USA. rachael.french@ucsf.edu
Heberlein
Ulrike
U
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D004560:Electricity; D000431:Ethanol / Q000633:toxicity*; D020868:Gene Silencing / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014835:Volatilization / Q000187:drug effects
D029721:Drosophila Proteins; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3