title: Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2-mediated antioxidant response.
abstract: Ataxia telangiectasia (A-T) is a rare incurable neurodegenerative disease caused by biallelic mutations in the gene for ataxia-telangiectasia mutated (ATM). The lack of a functional ATM kinase leads to a pleiotropic phenotype, and oxidative stress is considered to have a crucial role in the complex physiopathology. Recently, steroids have been shown to reduce the neurological symptoms of the disease, although the molecular mechanism of this effect is largely unknown. In the present study, we have demonstrated that dexamethasone treatment of A-T lymphoblastoid cells increases the content of two of the most abundant antioxidants [glutathione (GSH) and NADPH] by up to 30%. Dexamethasone promoted the nuclear accumulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 to drive expression of antioxidant pathways involved in GSH synthesis and NADPH production. The latter effect was via glucose 6-phosphate dehydrogenase activation, as confirmed by increased enzyme activity and enhancement of the pentose phosphate pathway rate. This evidence indicates that glucocorticoids are able to potentiate antioxidant defenses to counteract oxidative stress in ataxia telangiectasia, and also reveals an unexpected role for dexamethasone in redox homeostasis and cellular antioxidant activity.
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Biagiotti
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Menotta
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Orazi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Spapperi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Brundu
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fraternale
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Luigia
authors.initials: L
authors.lastname: Rossi
authors.affiliation: Department of Clinical and Molecular Medicine, University 'La Sapienza', Roma, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Chessa
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D009249:NADP / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D005938:Glucocorticoids; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D009249:NADP; D003907:Dexamethasone; D005954:Glucosephosphate Dehydrogenase; D064007:Ataxia Telangiectasia Mutated Proteins; D005978:Glutathione
keywords: ataxia telangiectasia; glucocorticoids; molecular cell biology; nuclear factor 2; oxidative stress