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 familial amyotrophic lateral sclerosis (FALS). In different kindreds, harboring different mutations, the duration of illness tends to be similar for a given mutation. For example, patients inheriting a substitution of valine for alanine at position four (A4V) average a 1.5 year life expectancy after the onset of symptoms, whereas patients harboring a substitution of arginine for histidine at position 46 (H46R) average an 18 year life expectancy after disease onset. Here, we examine a number of biochemical and biophysical properties of nine different FALS variants of SOD1 polypeptides, including enzymatic activity (which relates indirectly to the affinity of the enzyme for copper), polypeptide half-life, resistance to proteolytic degradation and solubility, in an effort to determine whether a specific property of these enzymes correlates with clinical progression. We find that although all the mutants tested appear to be soluble, the different mutants show a remarkable degree of variation with respect to activity, polypeptide half-life and resistance to proteolysis. However, these variables do not stratify in a manner that correlates with clinical progression. We conclude that the basis for the different life expectancies of patients in different kindreds of sod1-linked FALS may result from an as yet unidentified property of these mutant enzymes.
Department of Pathology, Johns Hopkins School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA,
T
T
Ratovitski
L B
LB
Corson
J
J
Strain
P
P
Wong
D W
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Cleveland
V C
VC
Culotta
D R
DR
Borchelt
D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D019556:COS Cells; D002498:Centrifugation; D003300:Copper / Q000378:metabolism; D018450:Disease Progression; D019286:Endopeptidase K / Q000378:metabolism; D005192:Family Health; D014644:Genetic Variation; D005998:Glycine / Q000235:genetics; D006639:Histidine / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011485:Protein Binding; D012995:Solubility; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D014407:Tumor Cells, Cultured
C000606290:SOD1 protein, human; D006639:Histidine; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019286:Endopeptidase K; D005998:Glycine