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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. Gordon^3,4,5,6

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 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 (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.

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

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

This article has been cited by other articles:

				X. Cao, S. V. Antonyuk, S. V. Seetharaman, L. J. Whitson, A. B. Taylor, S. P. Holloway, R. W. Strange, P. A. Doucette, J. S. Valentine, A. Tiwari, et al. Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis J. Biol. Chem., June 6, 2008; 283(23): 16169 - 16177. [Abstract] [Full Text] [PDF]

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