Genetically decreased spinal cord copper concentration prolongs life in a transgenic mouse model of amyotrophic lateral sclerosis.
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.
Kiaei
Mahmoud
M
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA. mak2026@med.cornell.edu
Bush
Ashley I
AI
Morrison
Brett M
BM
Morrison
John H
JH
Cherny
Robert A
RA
Volitakis
Irene
I
Beal
M Flint
MF
Gordon
Jon W
JW
D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000483:Alleles; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D001693:Biological Transport, Active; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003300:Copper / Q000032:analysis / Q000502:physiology*; D000073840:Copper-Transporting ATPases; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D013116:Spinal Cord / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072105:Superoxide Dismutase-1
C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D009419:Nerve Tissue Proteins; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases