The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1G93A Mouse Model for Motor Neuron Disease*

@article{ElKadi2010TheLA,
  title={The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1G93A Mouse Model for Motor Neuron Disease*},
  author={Ali Morsi El-Kadi and Virginie Bros-Facer and Wenhan Deng and Amelia Philpott and Eleanor Stoddart and Gareth T. Banks and Graham Stuart Jackson and Elizabeth M. C. Fisher and Michael R. Duchen and Linda Greensmith and Anthony L. Moore and Majid Hafezparast},
  journal={The Journal of Biological Chemistry},
  year={2010},
  volume={285},
  pages={18627 - 18639}
}
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼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… Expand
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References

SHOWING 1-10 OF 58 REFERENCES
Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex*
TLDR
A direct “gain-of-interaction” between mutant S OD1 and dynein is demonstrated, which may provide insights into the mechanism by which mutant SOD1 could contribute to a defect in retrograde axonal transport or other dyneIn functions. Expand
A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice
TLDR
It is proposed that impaired axonal transport is a prime cause of neuronal death in neurodegenerative disorders such as ALS and crossing S OD1G93A mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1G 93A mice. Expand
A dynein mutation attenuates motor neuron degeneration in SOD1G93A mice
TLDR
This study confirms that mechanisms associated with dynein such as retrograde axonal transport may play an important role in SOD1(G93A-) toxicity on motor neurons and cross-bred S OD1( G93A) with Cra1/+ mice shows an attenuated decline of both motor activity and body weight and an increase of survival time. Expand
Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content.
TLDR
Time-lapse microscopy is used to monitor for the first time the effect of mutant S OD1 on fast axonal transport (FAT) of bona fide cargoes in living neurons and finds that mutant SOD1 damages transport of both mitochondria and MBOs, and that the precise details of this damage are cargo-specific. Expand
Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death
TLDR
Findings support a noncell autonomous, excitotoxic contribution from proprioceptive sensory neurons that modestly accelerates disease onset in inherited ALS. Expand
Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation*
TLDR
It is suggested that formation of large inclusions depends upon association of the abnormal SOD1s with the dynein motor, and this interaction could propagate a toxic effect that ultimately causes motor neuron death in ALS. Expand
Proprioceptive Sensory Neuropathy in Mice with a Mutation in the Cytoplasmic Dynein Heavy Chain 1 Gene
TLDR
In vivo evidence is provided that distinct mutations in cytoplasmic dynein can either result in a pure sensory neuropathy or in a sensory Neuropathy with motor neuron involvement. Expand
Mutated Human SOD1 Causes Dysfunction of Oxidative Phosphorylation in Mitochondria of Transgenic Mice*
TLDR
The findings suggest that G93A-mutated hSOD1 in mitochondria may cause mitochondrial defects, which contribute to precipitating the neurodegenerative process in motor neurons. Expand
Cytochrome c Association with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice
TLDR
A mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program is suggested. Expand
Mitochondrial dysfunction and amyotrophic lateral sclerosis
TLDR
In transgenic mice expressing mutant Cu,Zn‐superoxide dismutase (SOD1), the antioxidant enzyme associated with familial ALS (FALS), mitochondrial abnormalities precede the disease onset, suggesting that mitochondrial dysfunction is causally involved in the pathogenesis of SOD1‐FALS. Expand
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