Regulation of huntingtin-polyQ aggregation by glucose transporters and saccharide-binding receptors during aging in Drosophila.

Abstract

Saccharides and responsive signaling pathways are important regulators of physiological and pathological processes. Saccharides can exert these functions via dedicated intracellular transporters and through binding to cellular sensors, such as saccharide-binding receptors. Glucose homeostasis and saccharide signaling are emerging as important regulators of neurodegeneration. Here, we utilized a Drosophila model of Huntington's disease to examine the role of Glut1 (homologous to multiple human glucose transporters) and saccharide-binding receptors. We find that Glut1 knockdown increases the amount of huntingtin-polyQ protein aggregates during aging, whereas Glut1 upregulation has converse effects. RNAi screening identifies several saccharide-binding receptors that either increase or decrease the levels of huntingtin-polyQ protein aggregates. In particular, pathogenic polyglutamine aggregates are reduced by knockdown of the lectin domain-containing G-protein coupled receptor Cirl (Calcium-independent receptor for α-latrotoxin), orthologous to human ADGRL1 and ADGRL2. These findings indicate that glucose transporters and saccharide-binding receptors regulate proteostasis and neurodegeneration during aging.