Human Molecular Genetics, Vol 8, 1451-1460, Copyright © 1999 by Oxford University Press
T Ratovitski, LB Corson, J Strain, P Wong, DW Cleveland, VC Culotta and DR Borchelt
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.
ARTICLES
Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds
Department of Pathology, Johns Hopkins School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA,
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