Abstract
Mutations in the Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS) by gain of an aberrant function that is not yet well understood. The role of Cu(2+) in mediating the toxicity of mutant SOD1 has been earnestly contested. We tested the in vivo effects of genetically induced copper deprivation on the ALS phenotype of transgenic mice expressing G86R mutant mouse SOD1, a protein that fails to incorporate Cu(2+) in its active site. Genetically copper-deficient SOD1(G86R) transgenic mice were produced by mating SOD1(G86R) males to female carriers of the X-linked mottled/brindled (Mobr) mutation. We found that the Mobr allele causes a severe ( approximately 60%) depletion of spinal cord copper levels; however, despite the burden of double genetic lesions, it lengthens the lives of SOD1(G86R) transgenic mice by 9%. These findings provide evidence supporting a role for copper in the pathogenesis of FALS linked to SOD1 mutations.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphatases / deficiency
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / physiology*
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Alleles
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Amino Acid Substitution
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Amyotrophic Lateral Sclerosis / enzymology
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Amyotrophic Lateral Sclerosis / genetics
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Animals
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Binding Sites
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Biological Transport, Active
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Brain / enzymology
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Brain Chemistry
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Cation Transport Proteins / deficiency
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Cation Transport Proteins / genetics
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Cation Transport Proteins / physiology*
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Copper / analysis
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Copper / physiology*
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Copper-Transporting ATPases
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Crosses, Genetic
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Disease Models, Animal
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Enzyme Induction
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Female
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Longevity / genetics*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Mice, Transgenic
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Mutation, Missense
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Phenotype
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Spinal Cord / chemistry*
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Spinal Cord / enzymology
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Spinal Cord / pathology
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Superoxide Dismutase / deficiency
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Superoxide Dismutase / genetics
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Superoxide Dismutase / physiology*
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Superoxide Dismutase-1
Substances
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Atp7a protein, mouse
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Cation Transport Proteins
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Nerve Tissue Proteins
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Copper
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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Adenosine Triphosphatases
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Copper-Transporting ATPases