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The Journal of Neuroscience, September 8, 2004, 24(36):7945-7950; doi:10.1523/JNEUROSCI.2000-04.2004

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Neurobiology of Disease
Genetically Decreased Spinal Cord Copper Concentration Prolongs Life in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Mahmoud Kiaei,1,3,4 Ashley I. Bush,2,7 Brett M. Morrison,3,4 John H. Morrison,3,4 Robert A. Cherny,7 Irene Volitakis,7 M. Flint Beal,1 and Jon W. Gordon3,4,5,6

1Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, 2Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital East, Charlestown, Massachusetts 02129, 3Neurobiology of Aging Laboratories and 4Fishberg Research Center for Neurobiology and Departments of 5Geriatrics and Adult Development and 6Obstetrics/Gynecology and Reproductive Science, Mount Sinai School of Medicine, New York, New York 10029, and 7Mental Health Research Institute of Victoria and Department of Pathology, The University of Melbourne, Parkville, Victoria, 3052, Australia

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 Cu2+ 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 Cu2+ in its active site. Genetically copper-deficient SOD1G86R transgenic mice were produced by mating SOD1G86R males to female carriers of the X-linked mottled/brindled (Mobr) mutation. We found that the Mobr allele causes a severe (~60%) depletion of spinal cord copper levels; however, despite the burden of double genetic lesions, it lengthens the lives of SOD1G86R transgenic mice by 9%. These findings provide evidence supporting a role for copper in the pathogenesis of FALS linked to SOD1 mutations.

Key words: superoxide dismutase; amyotrophic lateral sclerosis; copper; mottled/brindled; neurodegeneration; motor neuron

Received May 24, 2004; revised July 12, 2004; accepted August 1, 2004.




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