Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9429287 | Neuroscience Letters | 2005 | 5 Pages |
Abstract
Mutations to the copper, zinc superoxide dismutase (SOD) gene are responsible for 2-3% of amyotrophic lateral sclerosis (ALS) cases. These mutations result in the protein having a reduced affinity for zinc. SOD becomes toxic to motor neurons when zinc is missing from its active site. Recently, high dosages of zinc (75 and 375Â mg/kg/day) have been paradoxically reported to increase the death of G93A-mutant SOD transgenic mice [G.J. Groeneveld, J. de Leeuw van Weenen, F.L. van Muiswinkel, H. Veldman, J.H. Veldink, J.H. Wokke, P.R. Bar, L.H. van den Berg, Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis, Neurosci. Lett. 352 (2003) 175-178]. In contrast, we have found that moderate supplementation of zinc (â¼12Â mg/kg/day) delayed death in G93A-mutant SOD mice by 11 days compared to mice on a zinc-deficient diet. Supplementing zinc with even 18Â mg/kg/day resulted in a more rapid death of some mice, consistent with the results of Groenevelt et al. However, large amounts of zinc competitively inhibit copper absorption, which inhibits the copper-dependent ceruloplasmin, and can cause a lethal anemia. We found that supplementing the 18Â mg/kg/day dosage of zinc with 0.3Â mg/kg/day of copper prevented the early death from zinc treatment alone. These data support a role for moderate levels of dietary zinc potentially protecting against the toxicity of ALS-associated SOD and the protection does not result from depleting copper.
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Authors
Irina P. Ermilova, Vladimir B. Ermilov, Mark Levy, Emily Ho, Cliff Pereira, Joseph S. Beckman,