Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis

Significance Statement

Degeneration of spinal motor neurons leads to muscle weakness and pathogenesis of diseases such as Amyotrophic Lateral Sclerosis (ALS). Glutathione peroxidase 4 (Gpx4), an antioxidant defense enzyme in repairing oxidative damage to lipids, is a key regulator of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. In this study, we showed that, conditional ablation of Glutathione peroxidase 4 in neurons of adult mice resulted in rapid onset and progression of paralysis driven by a dramatic degeneration of motor neurons in spinal cord. We also showed that spinal motor neuron degeneration induced by Gpx4 ablation exhibited features of ferroptosis. Our results indicate that ferroptosis inhibition by Glutathione peroxidase 4 is essential for motor neuron health and survival in vivo, suggesting that increased activity/level of Glutathione peroxidase 4 may protect against degeneration of spinal motor neurons.

About the author

Dr. Qitao Ran is an Associate Professor at Department of Cellular & Structural Biology of the University of Texas Health Science Center at San Antonio. Dr. Ran received his PhD degree from Peking Union Medical College (Beijing, China) in 1995. He conducted postdoctoral research at Baylor College of Medicine (Houston, Texas) from 1995 to 2000, and continued his research at the University of Texas Health Science Center at San Antonio afterwards. Dr. Ran was appointed Assistant Professor at Department of Cellular & Structural Biology and Barshop Institute for Longevity and Aging Research of the University of Texas Health Science Center at San Antonio in 2006. Dr. Ran was also appointed Research Health Scientist at South Texas Veterans Health Care System in 2007. The main research interest of Dr. Ran’s lab is to interrogate the mechanisms of neurodegenerative diseases such as Alzheimer’s disease and ALS as well as aging.

Figure Legend: Spinal motor neuron loss induced by Glutathione peroxidase 4 ablation in neurons.

A. Fluorescence microscopy images of spinal cord section from a control Gpx4NIKO mouse without tamoxifen treatment to ablate Glutathione peroxidase 4.

B. Fluorescence microscopy images of spinal cord section from a tamoxifen-treated Gpx4NIKO mouse at day 6, showing the absence of ChAT positive motor neurons.

Journal Reference

J Biol Chem. 2015 Nov 20;290(47):28097-106.

Chen L¹, Hambright WS¹, Na R¹, Ran Q².

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From the Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229 and.
From the Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229 and the Research Service, South Texas Veterans Health Care System, San Antonio, Texas 78229 [email protected].

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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 Glutathione peroxidase 4 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 Glutathione peroxidase 4 as a ferroptosis inhibitor, spinal motor neuron degeneration induced by Glutathione peroxidase 4 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 Glutathione peroxidase 4 ablation. Also, lipid peroxidation and mitochondrial dysfunction appeared to be involved in ferroptosis of motor neurons induced by Glutathione peroxidase 4 ablation. Taken together, the dramatic motor neuron degeneration and paralysis induced by Glutathione peroxidase 4 ablation suggest that ferroptosis inhibition by Glutathione peroxidase 4 is essential for motor neuron health and survival in vivo.

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