Extracellular adenosine functions as a stress signaling molecule
Extracellular adenosine (Ado) was formerly considered a defensive metabolite with general protective effects on tissues. However, prolonged adenosine signaling in chronic diseases may exacerbate tissue damage. A detailed study of the nervous system in mammals shows that Ado maintains cell viability at a low degree of damage, whereas it has the opposite effect at more intense damage.
Figure: Summary model of Ado signaling under stress response. Under a non-stress condition, the activated AdoR and Mod(mdg4) reduce Hsp70 production. In contrast, decreased Ado signaling under a stress condition resulted in Hsp70 production, which in turn enhanced cytotoxic stress tolerance.
In our study, we focused on the effect of the Ado stress signal on the pathological effects of the expression of the mutant huntingtin gene (mHTT) in the nervous system of Drosophila. This mutation causes Huntington's disease, which is a human hereditary neurodegenerative disorder. Drosophila larvae or adult flies expressing mHTT have low viability. We found that blocking the adenosine signal sharply improves the survival and overall physiological state of the experimental flies, while amplifying the signal worsens the condition. In subsequent experiments, we compared the gene expression profiles of individuals with mutations in the Ado receptor and transporters and revealed other genes related to this phenomenon. The adenosine receptor regulates the mod(mdg4) gene, which in turn regulates the heat shock protein 70 (Hsp70), thus creating a signaling cascade that can decrease the protein aggregation of mHTT in the fly brains as well as modulate the susceptibility to heat-shock and oxidative stress.
This study provides important insights into the molecular mechanisms capable of regulating the formation of mHTT protein aggregates and other stress conditions in Drosophila. These mechanisms could elucidate the role of Ado in influencing the pathogenesis of many diseases.
Lin Y.-H., Maaroufi H., Kučerová L., Rouhová L., Filip T., Žurovec M. (2021) Adenosine receptor ant its downstream targets, Mod(mdg4) and Hsp70, work as a signaling pathway modulating cytotoxic damage in Drosophila. Frontiers in Cell and Developmental Biology 9: article number: 651367. https://doi.org/10.3389/fcell.2021.651367