Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice.

ABSTRACT: Degeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degeneration of ALS remains unclear. Glutathione peroxidase 4 (Gpx4) is a key enzyme in suppressing ferroptosis by reducing phospholipid hydroperoxides in membranes. To assess the effect of increased protection against ferroptosis on motor neuron disease, we generated SOD1^G93AGPX4 double transgenic mice by cross-breeding GPX4 transgenic mice with SOD1^G93A mice, a widely used ALS mouse model. Compared with control SOD1^G93A mice, both male and female SOD1^G93AGPX4 mice had extended lifespans. SOD1^G93AGPX4 mice also showed delayed disease onset and increased motor function, which were correlated with ameliorated spinal motor neuron degeneration and reduced lipid peroxidation. Moreover, cell toxicity induced by SOD1^G93A was ameliorated by Gpx4 overexpression and by chemical inhibitors of ferroptosis in vitro. We further found that the anti-ferroptosis defense system in spinal cord tissues of symptomatic SOD1^G93A mice and sporadic ALS patients might be compromised due to deficiency of Gpx4. Thus, our results suggest that ferroptosis plays a key role in motor neuron degeneration of ALS.

SUBMITTER: Chen L 

PROVIDER: S-EPMC8213805 | biostudies-literature |

REPOSITORIES: biostudies-literature