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The Gpx4NIKO Mouse Is a Versatile Model for Testing Interventions Targeting Ferroptotic Cell Death of Spinal Motor
Robert Cole Evans1, Liuji Chen1, Ren Na1
1Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
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.
Insights
This study shows that inhibiting ferroptosis can reduce motor neuron death in a mouse model of ALS. The Gpx4NIKO mouse model is a versatile tool for developing new treatments for motor neuron diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Motor neuron diseases like ALS involve motor neuron degeneration.
- Ferroptosis, an iron-dependent cell death, is increasingly implicated in neurodegeneration.
- The Gpx4NIKO mouse model, with ablated glutathione peroxidase 4 (GPX4), mimics ALS and involves ferroptosis.
Purpose of the Study:
- To investigate the role of ferroptosis in the Gpx4NIKO mouse model of ALS.
- To evaluate the therapeutic potential of targeting ferroptosis for motor neuron diseases.
- To explore the involvement of mitochondrial reactive oxygen species (mtROS) in spinal motor neuron ferroptosis.
Main Methods:
- Administered tamoxifen to Gpx4NIKO mice to ablate GPX4 in neurons.
- Used a chemical inhibitor of ferroptosis to treat Gpx4NIKO mice.
- Generated mild and severe paralytic models by adjusting tamoxifen dosage.
- Assessed the effect of peroxiredoxin 3 overexpression on motor neuron symptoms.
Main Results:
- Ferroptosis inhibition attenuated paralytic symptoms and spinal motor neuron death in Gpx4NIKO mice.
- Adjusting tamoxifen dosage allowed for the creation of a mild paralytic model.
- Overexpression of peroxiredoxin 3 ameliorated symptoms in the mild model but not the severe model.
Conclusions:
- Ferroptosis plays a significant role in spinal motor neuron death in the Gpx4NIKO mouse model.
- The Gpx4NIKO mouse is a valuable and adaptable model for testing interventions targeting ferroptotic motor neuron death.
- mtROS contribute to ferroptosis in spinal motor neurons, with varying impact depending on disease severity.
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