Glycogen synthase kinase-3/Shaggy mediates ethanol-induced excitotoxic cell death of Drosophila olfactory neurons

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 49; pp. 20924 - 20929
• Main Authors: French, Rachael L, Heberlein, Ulrike
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08-12-2009; National Acad Sciences
• Subjects: Alcohol use; Alcoholism; Animals; Apoptosis; Biological Sciences; Cell death; Cell Death - drug effects; Drosophila; Drosophila melanogaster; Drosophila melanogaster - cytology; Drosophila melanogaster - drug effects; Drosophila melanogaster - enzymology; Drosophila Proteins - metabolism; Effects; Electricity; Ethanol; Ethanol - toxicity; Gene Silencing - drug effects; Genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; glycogen synthase kinase-3; Insect antennae; Insects; Lithium - pharmacology; N methyl D aspartate receptors; Neurons; neurotoxicity; Neurotoxins - toxicity; olfactory neurons; olfactory organs; Olfactory Receptor Neurons - drug effects; Olfactory Receptor Neurons - enzymology; Olfactory Receptor Neurons - pathology; Palps; Protective effects; protein kinases; Receptors, N-Methyl-D-Aspartate - metabolism; Sequence Homology, Amino Acid; Shaggy protein; Volatilization - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0910813106

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)β, Shaggy, is required for ethanol-induced apoptosis. Consistent with this requirement, the GSK-3β 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-3β in programmed cell death.