SUPEROXIDE-DISMUTASE-1 SUBUNITS WITH MUTATIONS LINKED TO FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS DO NOT AFFECT WILD-TYPE SUBUNIT FUNCTION

Mutations in superoxide dismutase 1 (SOD1) have been linked to familia l amyotrophic lateral sclerosis, a dominantly inherited motor neuron d isorder of midlife. Because SOD1 is a homodimeric enzyme, dimerization of mutant and wild-type SOD1 subunits could dominantly alter the acti vity, stability, or localization of wild-type SOD1 subunits. To explor e these possibilities, we used transient and stable gene transfection to express high levels of either of two mutant human SOD1 subunits in the presence of limited levels of wild-type mouse and/or human SOD1 su bunits. Although both mutant subunits displayed diminished half-lives and free radical scavenging activities, their presence caused no chang e in the half-life or activity of wild-type SOD1 subunits. Our data in dicate that mutant subunits do not dominantly affect the function of w ild-type SOD1 subunits. These findings, together with observations tha t many mutant SOD1 subunits retain significant stability and activity, suggest that motor neuron damage in familial amyotrophic lateral scle rosis is caused by the acquisition of injurious properties by mutant S OD1 subunits.