Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.
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.
Ermilova
Irina P
IP
Linus Pauling Institute, Environmental Health Sciences Center, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
Ermilov
Vladimir B
VB
Levy
Mark
M
Ho
Emily
E
Pereira
Cliff
C
Beckman
Joseph S
JS
D000690:Amyotrophic Lateral Sclerosis / Q000178:diet therapy* / Q000235:genetics / Q000401:mortality; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight / Q000187:drug effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic / Q000502:physiology; D012018:Reflex / Q000502:physiology; D012737:Sex Factors; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors; D015032:Zinc / Q000627:therapeutic use*
C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D015032:Zinc