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.
Ratovitski
T
T
Department of Pathology, Johns Hopkins School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA,
Corson
L B
LB
Strain
J
J
Wong
P
P
Cleveland
D W
DW
Culotta
V C
VC
Borchelt
D R
DR
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