Abstract
Dysregulation of adenosine (Ado) homeostasis has been observed in both rodent models and human patients of Huntington’s disease (HD). However, the underlying mechanisms of Ado signaling in HD pathogenesis are still unclear. In the present study, we used a Drosophila HD model to examine the concentration of extracellular Ado (e-Ado) as well as the transcription of genes involved in Ado homeostasis and found similar alterations. Through candidate RNAi screening, we demonstrated that silencing the expression of adenosine receptor (adoR) and equilibrative nucleoside transporter 2 (ent2) not only significantly increases the survival of HD flies but also suppresses both retinal pigment cell degeneration and the formation of mutant Huntingtin (mHTT) aggregates in the brain. We compared the transcription profiles of adoR and ent2 mutants by microarray analysis and identified a downstream target of AdoR signaling, mod(mdg4), which mediates the effects of AdoR on HD pathology in Drosophila. Our findings have important implications for the crosstalk between Ado signaling and the pathogenic effects of HD, as well as other human diseases associated with polyglutamine aggregation.