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Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke

PUBLICATION: 
Journal Article
Authors: 
Ishraq Alim, Joseph T. Caulfield, Yingxin Chen, Vivek Swarup, Daniel H. Geschwind, Elena Ivanova, Javier Seravalli, Youxi Ai, Lauren H. Sansing, Emma J. Ste.Marie, Robert J. Hondal, Sushmita Mukherjee, John W. Cave, Botir T. Sagdullaev, Saravanan S. Karuppagounder, Rajiv R. Ratan
Year Published: 
2019
Publisher: 
Cell. 2019 May 16;177(5):1262-1279.e25. doi: 10.1016/j.cell.2019.03.032. Epub 2019 May 2.
Identifiers: 
PMID: 31056284 | DOI: 10.1016/j.cell.2019.03.032
Abstract on CellPress

Abstract

Highlights

  • Ferroptotic stimuli drive inadequate transcription of protective selenoproteins
  • Selenium (Se) enhances adaptive transcription to protect cells from ferroptosis
  • Se induces a protective selenome via DNA binding of TFAP2c and Sp1
  • A selenocysteine-containing peptide, Tat SelPep, improves outcomes after stroke

Summary

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-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.
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