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Updated: Aug 18, 2026
Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
Published on: January 7, 2019
Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit
Rohini Kuner1, Anthony J Groom, Iris Bresink
1Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca(2+) permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca(2+) influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans.
Insights
Altered calcium permeability in AMPA receptors contributes to spinal motoneuron degeneration in Amyotrophic Lateral Sclerosis (ALS). This finding suggests new therapeutic targets for sporadic ALS, independent of superoxide metabolism.
Area of Science:
- Neuroscience
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting spinal motoneurons.
- While mutated superoxide dismutase 1 (SOD1) is linked to familial ALS, its role in sporadic ALS is unclear.
- Existing research suggests factors beyond superoxide metabolism contribute to sporadic ALS pathogenesis.
Purpose of the Study:
- To investigate the role of increased calcium permeability in AMPA receptors in spinal motoneuron degeneration.
- To determine if altered AMPA receptor function contributes to the pathogenesis of sporadic ALS.
- To examine the interaction between altered AMPA receptors and mutated SOD1 in disease progression.
Main Methods:
- Transgenic mice expressing GluR-B(N)-containing AMPA receptors with increased Ca(2+) permeability were utilized.
- Assessment of neuronal degeneration, motor function decline, and survival rates in these mice.
- Co-expression of mutated human SOD1 in transgenic mice to evaluate combined effects on disease progression.
Main Results:
- Transgenic expression of Ca(2+)-permeable AMPA receptors induced late-onset spinal motoneuron degeneration and motor decline.
- Neuronal death progressed throughout life, mimicking slow neurodegenerative disorders.
- Co-expression of mutated SOD1 significantly accelerated disease progression, worsened motor deficits, and reduced survival.
Conclusions:
- Persistently elevated Ca(2+) influx through AMPA channels is linked to progressive motor decline and spinal motoneuron degeneration.
- Functionally altered AMPA receptors may be causally involved in the pathogenesis of sporadic ALS.
- These findings highlight potential therapeutic targets for ALS unrelated to superoxide metabolism.
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