Journal
CELL
Volume 177, Issue 5, Pages 1262-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.03.032
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Funding
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Burke Foundation
- Sperling Center for Hemorrhagic Stroke Recovery at the Burke Medical Research Institute
- NIH [P01 NIA AG014930, R01-EY026576, 5R01 MH110927, 5R01 MH109912, 5U01 MH105991, 5R01 MH100027]
- Larry L. Hillblom Foundation
- Laster Program in Peptide Therapeutics
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Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-depench-nf ferroptotic death as well as cell death induced toxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to cell death and improves function when delivered after hemorrhagic or ischemic stroke.
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