Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/31760
Title: The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration
Authors: Varadarajan, S.
Breda, Carlo
Smalley, Joshua L.
Butterworth, Michael
Farrow, S. N.
Giorgini, Flaviano
Cohen, G. M.
First Published: 6-Feb-2015
Publisher: Nature Publishing Group
Citation: Cell Death and Differentiation (2015), 1–9
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 pro-survival 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 (GDF15) plays an important role downstream of glucocorticoid signaling in antagonising 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.
DOI Link: 10.1038/cdd.2015.1
ISSN: 1350-9047
eISSN: 1476-5403
Links: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd20151a.html
http://hdl.handle.net/2381/31760
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Archived with reference to SHERPA/RoMEO. Copyright 2015 the authors. Version of record: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd20151a.html
Appears in Collections:Published Articles, Dept. of Genetics

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