Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds

Mutations in superoxide dismutase 1 (SOD1) polypeptides cause a form of fam ilial amyotrophic lateral sclerosis (FALS), In different kindreds, harborin g different mutations, the duration of illness tends to be similar for a gi ven mutation. For example, patients inheriting a substitution of valine for alanine at position four (A4V) average a 1.5 year life expectancy after th e onset of symptoms, whereas patients harboring a substitution of arginine for histidine at position 46 (H46R) average an 18 year life expectancy afte r disease onset. Here, we examine a number of biochemical and biophysical p roperties of nine different FALS variants of SOD1 polypeptides, including e nzymatic activity (which relates indirectly to the affinity of the enzyme f or copper), polypeptide half-life, resistance to proteolytic degradation an d solubility, in an effort to determine whether a specific property of thes e enzymes correlates with clinical progression, We find that although all t he mutants tested appear to be soluble, the different mutants show a remark able degree of variation with respect to activity, polypeptide half-life an d resistance to proteolysis, However, these variables do not stratify in a manner that correlates with clinical progression. We conclude that the basi s for the different life expectancies of patients in different kindreds of sod1-linked FALS may result from an as yet unidentified property of these m utant enzymes.