Biagiotti Sara, Menotta Michele, Orazi Sara, Spapperi Chiara, Brundu Serena, Fraternale Alessandra, Bianchi Marzia, Rossi Luigia, Chessa Luciana, Magnani Mauro
Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Italy.
Department of Clinical and Molecular Medicine, University 'La Sapienza', Roma, Italy.
FEBS J. 2016 Nov;283(21):3962-3978. doi: 10.1111/febs.13901. Epub 2016 Oct 12.
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.
共济失调毛细血管扩张症（A-T）是一种罕见的、无法治愈的神经退行性疾病，由共济失调毛细血管扩张症突变基因（ATM）的双等位基因突变引起。功能性ATM激酶的缺乏导致多效性表型，氧化应激被认为在复杂的生理病理学中起关键作用。最近，类固醇已被证明可减轻该疾病的神经症状，尽管这种作用的分子机制在很大程度上尚不清楚。在本研究中，我们证明地塞米松处理A-T淋巴母细胞可使两种最丰富的抗氧化剂[谷胱甘肽（GSH）和NADPH]的含量增加高达30%。地塞米松促进转录因子核因子（红系衍生2）样2的核积累，以驱动参与GSH合成和NADPH产生的抗氧化途径的表达。后一种作用是通过葡萄糖6-磷酸脱氢酶激活实现的，酶活性增加和磷酸戊糖途径速率提高证实了这一点。这一证据表明，糖皮质激素能够增强抗氧化防御，以抵消共济失调毛细血管扩张症中的氧化应激，并且还揭示了地塞米松在氧化还原稳态和细胞抗氧化活性中的意外作用。
