Functional roles for redox genes in ethanol sensitivity in Drosophila

Abstract

Whilst the effects and associated costs of excessive alcohol consumption in the human population are obvious at one level, the roles played by genetic factors at the molecular level are still unclear. Drosophila melanogaster has an alcohol response comparable to humans and is used as a genetic model to study the functional roles of genes regulated in response to ethanol. In the current study, the biological processes associated with behavioural responses to acute alcohol exposure in Drosophila have been analysed using whole genome expression profiling. Ethanol response genes differentially expressed (a) at a single time point (2 h) and (b) in a time series (0-4 h) were identified using microarrays. In addition, a subset of differentially expressed genes was validated using behavioural sedation and recovery assays. The study shows that genes involved in redox processes, neuron development, and specific signalling and metabolic pathways (including glutathione metabolism) form part of the response to ethanol in Drosophila. Biological processes for the regulation of oxidative stress are the common functional denominator of many of the ethanol response genes identified. These upregulated genes work to rescue cells from oxidative stress and its consequences such as protein misfolding, apoptosis and ageing. In the current study, an enrichment of Drosophila genes linked to ageing is observed for the first time. The functional genomics data revealed by such studies can be used to predict transcription networks of ethanol response genes, but the future lies in mapping these networks to the human population, with the ultimate aim of identifying genetic factors for alcohol use disorders.

TSPO, a Mitochondrial Outer Membrane Protein, Controls Ethanol-Related Behaviors in Drosophila

“…Given the short exposure period of the flies to ethanol, the ROS effect is most likely due to its second messenger action [ 26 ] rather than due to a cell death mechanism. This is consistent with the recent report showing that expression of oxidative stress genes can be altered by ethanol exposure and their functions are essential for ethanol sensitivity [ 29 , 30 ]. It is possible that TSPO-deficiency induced ROS production could also participate in development of tolerance, but this effect must be mediated by cells other than neurons.…”

The Genetics of Alcohol Responses of Invertebrate Model Systems

“…A meta-analysis showed that only about 4% of the statistically most significant changes in expression (29 out of 737) were shared with two previous microarray studies (Morozova et al, 2006;Urizar, Yang, Edenberg, & Davis, 2007). Another group (Awofala, Davies, & Jones, 2012) also compared their analysis of mRNA abundance changes two hours after ethanol exposure to the microarray studies by Morozova et al (2006) and Urizar et al (2007). They report only a 9% overlap of their ethanol-response genes with the two other studies.…”

Identification of differentially expressed genes in female Drosophila antonietae and Drosophila meridionalisin response to host cactus odor

“…Ethanol produces oxidative stress by causing an imbalance in redox reactions and increases the formation of reactive oxygen species (ROS) [47,48]. The increase in ROS levels activates detoxification mechanisms that act as antioxidants and reduce the synthesis of ROS [49]. Glutathione metabolism is among the detoxification mechanisms involved in the response to ethanol and was shown to be activated in D. meridionalis in our study.…”

“…In D. antonietae , we found evidence for the activation of the Wnt pathway, which plays a central role in several developmental processes, including neurogenesis [57]. This pathway may also be linked to neuronal apoptosis, which can be a result of exposure to ethanol present in volatile compounds produced by cacti [49]. In contrast, the Notch pathway was activated in D. meridionalis .…”