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Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
Published on: January 7, 2019
Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice
L Siklós1, J I Engelhardt, M E Alexianu
1Department of Neurology, Baylor College of Medicine, Tex 77030, USA.
Abstract:
Transgenic mice with Cu,Zn superoxide dismutase (SOD-1) mutations provide a unique model to examine altered Ca homeostasis in selectively vulnerable and resistant motoneurons. In degenerating spinal motoneurons of G93 A SOD-1 mice, developing vacuoles were filled with calcium, while calcium was gradually depleted from the cytoplasm and intact mitochondria. In oculomotor neurons, no degenerative changes, vacuolization, or increased calcium were noted. Motor axon terminals of interosseus muscle gradually degenerated and intracellular calcium was depleted. Oculomotor terminals of mutant SOD-1 mice were smaller and exhibited no degenerative changes, but did exhibit unique membrane-enclosed organelles containing calcium. Spinal motoneurons of SOD-1 mice were shown to have fewer calcium binding proteins, such as parvalbumin, compared with oculomotor neurons. These data suggest that the SOD-1 mutation is associated with impaired calcium homeostasis in motoneurons in vivo, with increased likelihood of degeneration associated with higher levels of intracellular calcium and lower to absent levels of calbindin-D28K and/or parvalbumin, and decreased likelihood of degeneration associated with minimally changed calcium and ample calbindin-D28K and/or parvalbumin.
Insights
Mutations in copper-zinc superoxide dismutase (SOD-1) disrupt calcium (Ca) homeostasis in spinal motoneurons, leading to degeneration. Resistant oculomotor neurons maintain normal Ca levels and avoid this fate.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Transgenic mouse models with mutated copper-zinc superoxide dismutase (SOD-1) are crucial for studying neurodegenerative diseases.
- Altered calcium (Ca) homeostasis is implicated in motoneuron vulnerability and degeneration.
Purpose of the Study:
- To investigate the role of SOD-1 mutations in Ca homeostasis in vulnerable and resistant motoneurons.
- To correlate intracellular Ca levels and calcium-binding proteins with motoneuron degeneration.
Main Methods:
- Analysis of transgenic G93A SOD-1 mice.
- Examination of calcium distribution in spinal motoneurons and oculomotor neurons.
- Assessment of calcium-binding proteins, including parvalbumin and calbindin-D28K.
Main Results:
- Degenerating spinal motoneurons showed vacuolar calcium accumulation and cytoplasmic/mitochondrial calcium depletion.
- Oculomotor neurons exhibited no degeneration or significant calcium changes, but contained unique calcium-rich organelles.
- Spinal motoneurons had lower levels of calcium-binding proteins (parvalbumin) compared to oculomotor neurons.
Conclusions:
- SOD-1 mutations impair in vivo calcium homeostasis in motoneurons.
- Degeneration risk increases with higher intracellular calcium and lower calbindin-D28K/parvalbumin levels.
- Preserved calcium homeostasis, with ample calbindin-D28K/parvalbumin, is linked to motoneuron resistance.
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