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.
Highlights
Glutathione peroxidase 4 (GPX4) is shown to be a key inhibitor of ferroptosis, a cell death mechanism involving lipid reactive oxygen species
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
Glutathione Peroxidase 4 and Motor Neuron Degeneration cross-bred with Gpx4(f/f) mice to generate Gpx4NIKO mice and control Gpx4(f/f) mice used in this study
Summary
Glutathione peroxidase 4 (GPX4) is shown to be a key inhibitor of ferroptosis, a cell death mechanism involving lipid reactive oxygen species. 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. The dramatic motor neuron degeneration and paralysis induced by Gpx ablation suggest that ferroptosis inhibition by GPX4 is essential for motor neuron health and survival in vivo. Pathological inspection indicated that Gpx ablation led to a dramatic degeneration of motor neurons in the spinal cord but had no overt effect on neurons in the cerebral cortex. The robust motor neuron degeneration induced by Gpx ablation suggests that ferroptosis inhibition is essential for motor neuron health and survival in vivo
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have