THE COPPER CHAPERONE CCS DIRECTLY INTERACTS WITH COPPER ZINC SUPEROXIDE-DISMUTASE/

Dominantly inherited mutations in the gene encoding copper/zinc supero xide dismutase (SOD1) result in the fatal motor neuron disease familia l amyotrophic lateral sclerosis (FALS), These mutations confer a gain- of-function to SOD1 with neuronal degeneration resulting from enhanced free radical generating activity of the copper present in the mutant enzyme. The delivery of copper to SOD1 is mediated through a soluble f actor identified as the copper chaperone for SOD1 (CCS). Amino acid se quence alignment of SOD1 and CCS reveals a striking homology with cons ervation of the amino acids essential for mediating SOD1 homodimerizat ion. Here we demonstrate that CCS and SOD1 directly interact in vitro and in vivo and that this interaction is mediated via the homologous d omains in each protein. Importantly, CCS interacts not only with wild- type SOD1 but also with SOD1 containing the common missense mutations resulting in FALS. Our findings therefore reveal a common mechanism wh ereby different SOD1 FALS mutants may result in neuronal injury and su ggest a novel therapeutic approach in patients affected by this fatal disease.