Title | Protection by dietary zinc in ALS mutant G93A SOD transgenic mice. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Ermilova IP, Ermilov VB, Levy M, Ho E, Pereira C, Beckman JS |
Journal | Neurosci Lett |
Volume | 379 |
Issue | 1 |
Pagination | 42-6 |
Date Published | 2005 Apr 29 |
ISSN | 0304-3940 |
Keywords | Amyotrophic Lateral Sclerosis, Analysis of Variance, Animals, Behavior, Animal, Body Weight, Dietary Supplements, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Reflex, Sex Factors, Superoxide Dismutase, Time Factors, Zinc |
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 375 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 (approximately 12 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 18 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 18 mg/kg/day dosage of zinc with 0.3 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. |
DOI | 10.1016/j.neulet.2004.12.045 |
Alternate Journal | Neurosci. Lett. |
PubMed ID | 15814196 |
Grant List | ES00210 / ES / NIEHS NIH HHS / United States P01 AT002034 / AT / NCCIH NIH HHS / United States R01 NS033291 / NS / NINDS NIH HHS / United States |