Ablation of ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis [Molecular Bases of Disease]

September 23rd, 2015 by Chen, L., Hambright, W. S., Na, R., Ran, Q.

Glutathione peroxidase 4(Gpx4), an antioxidant defense enzyme 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 spinal cord, but had no overt neuron degeneration in cerebral cortex. Consistent with Gpx4′s role 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. Supplement of vitamin E, another inhibitor of ferroptosis, delayed the onset of paralysis and death induced by Gpx4 ablation. And 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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