SUPEROXIDE-DISMUTASE-1 WITH MUTATIONS LINKED TO FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS POSSESSES SIGNIFICANT ACTIVITY

Familial amyotrophic lateral sclerosis (FALS) has been linked to mutat ions in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1). As say by transient expression in primate cells of six FALS mutant enzyme s revealed a continuum of enzymatic activity bounded by the enzyme car rying the mutation Gly-85 --> Arg, which was inactive, and mutant enzy me G37R carrying the Gly-37 --> Arg change, which retained full specif ic activity but displayed a 2-fold reduction in polypeptide stability. The G37R mutant displayed similar properties in transformed lymphocyt es from an individual heterozygous for the G37R and wild-type SOD1 gen es; heterodimeric enzymes composed of mutant and wild-type subunits we re detected, but there was no measurable diminution in the stability a nd activity of the wild-type subunits. Thus, for mutants such as G37R, either surprisingly modest losses in activity (involving only the mut ant subunit) can yield motor neuron death, or alternatively, mutant SO D1 may acquire properties that injure motor neurons by one or more mec hanisms unrelated to the metabolism of oxygen radicals.