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

被引：1093

作者：

Alim, Ishraq ^{[1
,2
]}

Caulfield, Joseph T. ^{[1
,2
]}

Chen, Yingxin ^{[1
,2
]}

Swarup, Vivek ^{[3
,4
,5
]}

Geschwind, Daniel H. ^{[3
]}

Ivanova, Elena ^{[1
,2
]}

Seravalli, Javier ^{[6
,7
]}

Ai, Youxi ^{[8
]}

Sensing, Lauren H. ^{[8
]}

Ste Marie, Emma J. ^{[9
]}

Hondal, Robert J. ^{[9
]}

Mukherjee, Sushmita ^{[10
]}

Cave, John W. ^{[1
,2
]}

Sagdullaev, Botir T. ^{[1
,2
]}

Karuppagounder, Saravanan S. ^{[1
,2
]}

Ratan, Rajiv R. ^{[1
,2
]}

机构：

[1] Weill Cornell Med, Sperling Ctr Hemorrhag Stroke Recovery, Burke Neurol Inst, White Plains, NY 10605 USA

[2] Weill Cornell Med, Feil Family Brain & Mind Res Inst, New York, NY 10065 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[4] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA

[5] Inst Memory Impairments & Neurol Disorders UCI MI, Irvine, CA 92697 USA

[6] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA

[7] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA

[8] Yale Univ, Dept Neurol, Sch Med, New Haven, CT 06510 USA

[9] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA

[10] Weill Cornell Med, Dept Biochem, New York, NY 10065 USA

来源：

CELL | 2019年 / 177卷 / 05期

关键词：

INDUCED INTRACEREBRAL HEMORRHAGE; NEURONAL CELL-DEATH; GENETIC-CODE; AP-2; FAMILY; AMINO-ACID; IN-VITRO; PROTEIN; STRESS; BRAIN; EXPRESSION;

D O I：

10.1016/j.cell.2019.03.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1262 / +

页数：43

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