Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis
Open accessAbstract
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 that GPX4 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.
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Inducible or tissue-specific ablation of Gpx4 in mice provokes acute renal or hepatic injury, neurodegeneration, and defective immunity to infection, all preventable or mitigated by ferroptosis-inhibiting strategies.
“the inducible or tissue-specific ablation of Gpx4 in mice provokes a variety of pathological conditions, including acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [591]
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- Authors
- Chen, L., Hambright, W. S., Na, R., & Ran, Q.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Ran, Qitao
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 290
- Issue
- 47
- Pages
- 28097-28106
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4653669
- OpenAlex
- W2150146658
- Cited by
- 498
- References
- 25
- Citations by year
- 2026: 38 · 2025: 51 · 2024: 63 · 2023: 54 · 2022: 66 · 2021: 62 · 2020: 60 · 2019: 34 · 2018: 29 · 2017: 22 · 2016: 18 · 2015: 1
- FWCI
- 18.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- United States Department of Veterans Affairs
- Alzheimer's Association
- William & Ella Owens Medical Research Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- GPX4, ferroptosis, motor neuron degeneration, neuronal survival, conditional gene deletion, paralysis, spinal cord, lipid peroxidation, mitochondrial dysfunction, vitamin E, ERK activation, myelitis, oxidative lipid damage
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Glutathione Peroxidase, Motor Neurons, Paralysis, Spinal Cord, Cell Death, Reactive Oxygen Species, Mice, Knockout, Mice
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