title: Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis.
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 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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: Liuji
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: William Sealy
authors.initials: WS
authors.lastname: Hambright
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229.
authors.forename: Ren
authors.initials: R
authors.lastname: Na
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Research Service, South Texas Veterans Health Care System, San Antonio, Texas 78229. Electronic address: ran@uthscsa.edu.
authors.forename: Qitao
authors.initials: Q
authors.lastname: Ran
mesh_terms: D000818:Animals; D016923:Cell Death; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D010243:Paralysis / Q000201:enzymology*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D017382:Reactive Oxygen Species; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase
keywords: GPX4; cell death; ferroptosis; gene knockout; lipid peroxidation; motor neurons; muscle atrophy; neurodegeneration; paralysis