CHAPERONE-FACILITATED COPPER-BINDING IS A PROPERTY COMMON TO SEVERAL CLASSES OF FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS-LINKED SUPEROXIDE-DISMUTASE MUTANTS

Mutations in Cu, Zn superoxide dismutase (SOD1) cause the neurodegener ative disease familial amyotrophic lateral sclerosis from an as-yet-un identified toxic property(ies), Analysis in Saccharomyces cerevisiae o f a broad range of human familial amyotrophic lateral sclerosis-linked SOD1 mutants (A4V, G37R, G41D, H46R, H48Q, G85R, G93C, and I113T) rev eals one property common to these mutants (including two at residues t hat coordinate the catalytic copper): Each does indeed bind copper and scavenge oxygen-free radicals in vivo. Neither decreased copper bindi ng nor decreased superoxide scavenging activity is a property shared b y all mutants. The demonstration that shows that all mutants tested do bind copper under physiologic conditions supports a mechanism of SOD1 mutant-mediated disease arising from aberrant copper-mediated chemist ry catalyzed by less tightly folded land hence less constrained) mutan t enzymes. The mutant enzymes also are shown to acquire the catalytic copper in vivo through the action of CCS, a specific copper chaperone for SOD1, which in turn suggests that a search for inhibitors of this SOD1 copper chaperone may represent a therapeutic avenue.