Abstract
The degeneration and death of motor neurons lead to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Although the exact mechanism by which motor neuron degeneration occurs is not well understood, emerging evidence implicates the involvement of ferroptosis, an iron-dependent oxidative mode of cell death. We reported previously that treating Gpx4NIKO mice with tamoxifen to ablate the ferroptosis regulator glutathione peroxidase 4 (GPX4) in neurons produces a severe paralytic model resembling an accelerated form of ALS that appears to be caused by ferroptotic cell death of spinal motor neurons. In this study, in support of the role of ferroptosis in this model, we found that the paralytic symptoms and spinal motor neuron death of Gpx4NIKO mice were attenuated by a chemical inhibitor of ferroptosis. In addition, we observed that the paralytic symptoms of Gpx4NIKO mice were malleable and could be tapered by lowering the dose of tamoxifen, allowing for the generation of a mild paralytic model without a rapid onset of death. We further used both models to evaluate mitochondrial reactive oxygen species (mtROS) in the ferroptosis of spinal motor neurons and showed that overexpression of peroxiredoxin 3, a mitochondrial antioxidant defense enzyme, ameliorated symptoms of the mild but not the severe model of the Gpx4NIKO mice. Our results thus indicate that the Gpx4NIKO mouse is a versatile model for testing interventions that target ferroptotic death of spinal motor neurons in vivo.
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Funding
This work was supported in part by Merit Review Award I01 BX003507 from the United States (US) Department of Veterans Affairs Biomedical Laboratory Research and Development Program and by an award from Owens Foundation San Antonio to Q.R. Q.R. is also supported by grant AG064078 from NIA, NIH.
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R.C.E., L.C., R.N., K.Y., performed experiments; R.C.E. and Q.R. wrote the manuscript.
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Procedures for handling mice in this study were reviewed and approved by the Institutional Animal Care and Use Committees of the University of Texas Health San Antonio and the Audie Murphy Memorial Veterans Hospital, South Texas Veterans Health Care System. All methods were performed in accordance with the relevant guidelines and regulations.
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Evans, R.C., Chen, L., Na, R. et al. The Gpx4NIKO Mouse Is a Versatile Model for Testing Interventions Targeting Ferroptotic Cell Death of Spinal Motor Neurons. Neurotox Res 40, 373–383 (2022). https://doi.org/10.1007/s12640-021-00469-0
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DOI: https://doi.org/10.1007/s12640-021-00469-0