TitleProtection by dietary zinc in ALS mutant G93A SOD transgenic mice.
Publication TypeJournal Article
Year of Publication2005
AuthorsErmilova IP, Ermilov VB, Levy M, Ho E, Pereira C, Beckman JS
JournalNeurosci Lett
Volume379
Issue1
Pagination42-6
Date Published2005 Apr 29
ISSN0304-3940
KeywordsAmyotrophic 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.

DOI10.1016/j.neulet.2004.12.045
Alternate JournalNeurosci. Lett.
PubMed ID15814196
Grant ListES00210 / ES / NIEHS NIH HHS / United States
P01 AT002034 / AT / NCCIH NIH HHS / United States
R01 NS033291 / NS / NINDS NIH HHS / United States