Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis

Liuji Chen, William Sealy Hambright, Ren Na, Qitao Ran

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show thatGPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degeneration of motor neurons in the spinal cord but had no overt neuron degeneration in the cerebral cortex. Consistent with the role of GPX4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis, including no caspase-3 activation, no TUNEL staining, activation of ERKs, and elevated spinal inflammation. Supplementation with vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Gpx4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Gpx4 ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo.

Original languageEnglish (US)
Pages (from-to)28097-28106
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number47
DOIs
StatePublished - Nov 20 2015

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phospholipid-hydroperoxide glutathione peroxidase
Nerve Degeneration
Motor Neurons
Ablation
Paralysis
Neurons
Lipids
Chemical activation
Health
In Situ Nick-End Labeling
Vitamin E
Caspase 3
Cerebral Cortex
Lipid Peroxidation
Reactive Oxygen Species
Spinal Cord
Cell Death
Cell death
Antioxidants
Staining and Labeling

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. / Chen, Liuji; Hambright, William Sealy; Na, Ren; Ran, Qitao.

In: Journal of Biological Chemistry, Vol. 290, No. 47, 20.11.2015, p. 28097-28106.

Research output: Contribution to journalArticle

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