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 dismut ase (SOD1). There is in vitro evidence that certain SOD1 mutants, in a ddition to their normal dismutation function, show increased ability o f the enzyme to act as a peroxidase. This reaction is sensitive to inh ibition by copper chelators. To test this hypothesis in vivo, we admin istered the copper chelator d-penicillamine to a transgenic mouse mode l of familial amyotrophic lateral sclerosis overexpressing a mutated f orm of human SOD1. We demonstrate that oral administration of d-penici llamine is able to delay the onset of the disease and extend the survi val of these mice. Histological studies also showed a decreased loss o f facial motor neurons in d-penicillamine-treated transgenic mice, cor roborating the slower evolution of the disease in these animals. These results suggest that copper chelators may benefit patients with famil ial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene .