Abstract |
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute approximately 10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15-20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons.
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Authors | Ali Morsi El-Kadi, Virginie Bros-Facer, Wenhan Deng, Amelia Philpott, Eleanor Stoddart, Gareth Banks, Graham S Jackson, Elizabeth M C Fisher, Michael R Duchen, Linda Greensmith, Anthony L Moore, Majid Hafezparast |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 285
Issue 24
Pg. 18627-39
(Jun 11 2010)
ISSN: 1083-351X [Electronic] United States |
PMID | 20382740
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- SOD1 protein, human
- Sod1 protein, mouse
- Superoxide Dismutase
- Superoxide Dismutase-1
- Dyneins
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Topics |
- Animals
- Cytoplasm
(metabolism)
- Disease Models, Animal
- Dyneins
(genetics)
- Female
- Heterozygote
- Membrane Potentials
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Mitochondria
(metabolism)
- Motor Neuron Disease
(metabolism)
- Motor Neurons
(metabolism)
- Mutation
- Superoxide Dismutase
(genetics)
- Superoxide Dismutase-1
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