title: 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.
authors: Department of Molecular and Clinical Cancer Medicine and Pharmacology, University of Liverpool, Liverpool, UK.
authors: S
authors: S
authors: Varadarajan
authors: Department of Genetics, University of Leicester, Leicester, UK.
authors: C
authors: C
authors: Breda
authors: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors: J L
authors: JL
authors: Smalley
authors: MRC Toxicology Unit, University of Leicester, Leicester, UK.
authors: M
authors: M
authors: Butterworth
authors: Respiratory Therapy Area, GlaxoSmithKline, Stevenage, UK.
authors: S N
authors: SN
authors: Farrow
authors: Department of Genetics, University of Leicester, Leicester, UK.
authors: F
authors: F
authors: Giorgini
authors: Department of Molecular and Clinical Cancer Medicine and Pharmacology, University of Liverpool, Liverpool, UK.
authors: G M
authors: GM
authors: Cohen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D004330:Drosophila; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology
chemical_list: D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid
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