The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

Abstract

The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

Growth Differentiation Factor 15 Mediates Systemic Glucose Regulatory Action of T-Helper Type 2 Cytokines

“…The STAT6 pathway is important for maintaining cellular metabolism, particularly oxidative mitochondrial metabolism. However, GDF15 increases transcriptional regulation in response to various cellular stress and metabolic changes associated with mitochondrial dysfunction (41)(42)(43)(44). Based on these findings, we speculate that metabolic changes caused by STAT6 KO are associated with increased blood levels of GDF15.…”

Differential Levels of Endoplasmic Reticulum Stress in Peripheral Blood Mononuclear Cells from Patients with Sudden Sensorineural Hearing Loss

“…For example, GCs can inhibit ERS by promoting the secretion of correctly-folded proteins and degradation of misfolded proteins [ 33 ]. They also may selectively antagonize ER stress-induced apoptosis by reducing the transcription of growth differentiation factor 15 (GDF15) [ 34 ]. Furthermore, GCs can alleviate ERS response by inducing leucine zipper protein and interacting with CHOP to attenuate ERS-induced apoptotic cell death [ 11 , 32 ].…”

RecombinantHelicobacter pyloriCagA protein induces endoplasmic reticulum stress and autophagy in human cells

“…GR can disrupt protein machinery by regulating protein chaperons particularly heat shock proteins 70 and 90 and altering protein folding [52]. Also, several studies demonstrated that GR protects cells from ER stress-induced apoptosis via ameliorating ER stress by promoting the correct folding of proteins and enhancing the removal of misfolded proteins from the ER [53,54].…”