Metal-deficient SOD1 in amyotrophic lateral sclerosis

@article{Hilton2015MetaldeficientSI,
  title={Metal-deficient SOD1 in amyotrophic lateral sclerosis},
  author={James Hilton and Anthony R White and Peter J. Crouch},
  journal={Journal of Molecular Medicine (Berlin, Germany)},
  year={2015},
  volume={93},
  pages={481 - 487}
}
Mutations to the ubiquitous antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) were the first established genetic cause of the fatal, adult-onset neurodegenerative disease amyotrophic lateral sclerosis (ALS). It is widely accepted that these mutations do not cause ALS via a loss of antioxidant function, but elucidating the alternate toxic gain of function has proven to be elusive. Under physiological conditions, SOD1 binds one copper ion and one zinc ion per monomer to form a highly stable… Expand
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Assessment of metal concentrations in the SOD 1 G 93 A mouse model of 1 amyotrophic lateral sclerosis and its potential role in muscular denervation , with 2 particular focus on muscle tissue 3 4
Background: Amyotrophic lateral sclerosis (ALS) is among the most common of the motor neuron diseases, and arguably the most devastating. During the course of this fatal neurodegenerative disorder,Expand
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References

SHOWING 1-10 OF 78 REFERENCES
A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis.
TLDR
The zinc-deficient hypothesis offers a compelling explanation for how mutant S OD1s have an increased propensity to become selectively toxic to motor neurons and also explains how wild-type SOD1 can be toxic in nonfamilial ALS patients. Expand
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.
TLDR
This review draws together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of S OD1-associated fALS. Expand
ALS-causing SOD1 mutations promote production of copper-deficient misfolded species.
TLDR
It is established that wild-type SOD1 unfolds by a branched pathway involving a Zn-deficient monomer as the dominant intermediate of the major pathway, and with various metal-loaded and Cu- deficient dimers populated along the minor pathway. Expand
Insoluble Mutant SOD1 Is Partly Oligoubiquitinated in Amyotrophic Lateral Sclerosis Mice*
TLDR
It is proposed that ubiquitination occurs only after SOD1 aggregation and that oligoubiquitination may underline alternative mechanisms in disease pathogenesis. Expand
SOD1 and Amyotrophic Lateral Sclerosis: Mutations and Oligomerization
TLDR
It is shown here that these eleven SOD1 mutants, only when they are in the metal-free form, undergo the same general mechanism of oligomerization as found for the WT metal- free protein. Expand
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TLDR
Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported. Expand
Initiation and elongation in fibrillation of ALS-linked superoxide dismutase
TLDR
It is shown that a small amount of disulfide-reduced apo-SOD1 can rapidly initiate fibrillation of this exceptionally stable and highly structured protein under mild, physiologically accessible conditions, thus providing an unusual demonstration of a specific, physiological relevant form of a protein acting as an initiating agent for the fibrilation of another form of the same protein. Expand
Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis
TLDR
TTM is a copper-chelating drug that is capable of removing a copper ion from copper-thiolate clusters, such as SOD1, and it is found that TTM exerted therapeutic benefits in a mouse model of familial ALS. Expand
Decreased Zinc Affinity of Amyotrophic Lateral Sclerosis‐Associated Superoxide Dismutase Mutants Leads to Enhanced Catalysis of Tyrosine Nitration by Peroxynitrite
TLDR
The toxicity of ALS‐associated SOD mutants may be related to enhanced catalysis of protein nitration subsequent to zinc loss, and by acting as a high‐capacity zinc sink, NF‐L could foster the formation of zinc‐deficient SOD within motor neurons. Expand
Structural instability and Cu-dependent pro-oxidant activity acquired by the apo form of mutant SOD1 associated with amyotrophic lateral sclerosis.
TLDR
The possibility that the structural instability and the resultant Cu-dependent pro-oxidant activity of the apo form of mutant SOD1 may be one of the pathogenic mechanisms of ALS is raised. Expand
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