Figure 5.

The transrepression arm of glucocorticoid signaling antagonizes ER stress-induced upregulation of GDF15 and apoptosis, thereby diminishing mutant HTT-mediated neurodegeneration. Schematic representation depicting the induction of the UPR following various stress stimuli, resulting in prosurvival or apoptotic signaling pathways depending on the extent of stress. Here, we report a novel crosstalk between the glucocorticoid signaling pathway and the apoptotic arm of the UPR. Binding of glucocorticoids to their receptors can elicit transrepression and/or transactivation as part of their signaling cascade. Using a selective modulator of glucocorticoid signaling, GRT10, we confirm that the upregulation of GDF15 is an important event in the apoptotic arm of the UPR. Furthermore, by selective activation of the transrepression arm of glucocorticoid signaling, we demonstrate that downregulation of GDF15 is efficient in antagonizing ER stress-induced apoptosis, both in HeLa cells and also in a fruit fly model of HD. Exposure to glucocorticoids or a genetic inhibition of GDF15 ameliorated the disease pathology and was neuroprotective in adult HD flies and during development