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Volume 17, Number 22,
Issue of November 15, 1997
pp. 8756-8766
Mutant Superoxide Dismutase-1-Linked Familial Amyotrophic Lateral
Sclerosis: Molecular Mechanisms of Neuronal Death and
Protection
Received May 23, 1997; revised Aug. 18, 1997; accepted Aug. 26, 1997.
G. D. Ghadge1,
J. P. Lee2,
V. P. Bindokas2,
J. Jordan2,
L. Ma1,
R. J. Miller2, and
R. P. Roos1
Departments of 1 Neurology and
2 Pharmacological and Physiological Sciences, The
University of Chicago, Chicago, Illinois 60637
Mutations in human Cu/Zn superoxide dismutase-1 (SOD) cause ~20%
of cases of familial amyotrophic lateral sclerosis (FALS). We
investigated the mechanism of mutant SOD-induced neuronal degeneration by expressing wild-type and mutant SODs in neuronal cells by means of
infection with replication-deficient recombinant adenoviruses. Expression of two FALS-related mutant SODs (A4V and V148G) caused death
of differentiated PC12 cells, superior cervical ganglion neurons, and
hippocampal pyramidal neurons. Cell death included many features
typical of apoptosis. Death could be prevented by copper
(Cu2+) chelators, Bcl-2, glutathione, vitamin E, and
inhibitors of caspases. Mutant SOD-expressing PC12 cells had higher
rates of superoxide (O2 ) production under a variety
of conditions. The results support the hypothesis that mutant SOD
induced-neurodegeneration is associated with disturbances of neuronal
free radical homeostasis.
Key words:
familial amyotrophic lateral sclerosis;
superoxide
dismutase-1;
apoptosis;
recombinant adenovirus;
neurodegeneration;
oxidative stress
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