The Copper Chelator d-Penicillamine Delays Onset of Disease and Extends Survival in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis

A subpopulation of familial cases of amyotrophic lateral sclerosis has been linked to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). There is in vitro evidence that certain SOD1 mutants, in addition to their normal dismutation function, show increased ability of the enzyme to act...

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Bibliographic Details
Published in:The European journal of neuroscience 1997-07, Vol.9 (7), p.1548-1551
Main Authors: Hottinger, Andreas F., Fine, Eric G., Gurney, Mark E., Zurn, Anne D., Aebischer, Patrick
Format: Article
Language:English
Subjects:
amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - mortality
Amyotrophic Lateral Sclerosis - prevention & control
Animals
Brain Stem - pathology
Cell Count
Chelating Agents - pharmacology
Copper
copper chelators
d-penicillamine
Facial Nerve - pathology
Genes
Humans
Mice
Mice, Transgenic - genetics
Motor Neurons - pathology
Mutation
Penicillamine - pharmacology
superoxide dismutase
Superoxide Dismutase - genetics
Survival Analysis
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Summary:A subpopulation of familial cases of amyotrophic lateral sclerosis has been linked to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). There is in vitro evidence that certain SOD1 mutants, in addition to their normal dismutation function, show increased ability of the enzyme to act as a peroxidase. This reaction is sensitive to inhibition by copper chelators. To test this hypothesis in vivo, we administered the copper chelator d‐penicillamine to a transgenic mouse model of familial amyotrophic lateral sclerosis overexpressing a mutated form of human SOD1. We demonstrate that oral administration of d‐penicillamine is able to delay the onset of the disease and extend the survival of these mice. Histological studies also showed a decreased loss of facial motor neurons in d‐penicillamine‐treated transgenic mice, corroborating the slower evolution of the disease in these animals. These results suggest that copper chelators may benefit patients with familial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene.
ISSN:0953-816X
1460-9568
DOI:10.1111/j.1460-9568.1997.tb01511.x