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J. Biol. Chem., Vol. 277, Issue 49, 47551-47556, December 6, 2002
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From the The presence of intracellular aggregates
that contain Cu/Zn superoxide dismutase (SOD1) in spinal cord motor
neurons is a pathological hallmark of amyotrophic lateral sclerosis
(ALS). Although SOD1 is abundant in all cells, its half-life in motor neurons far exceeds that in any other cell type. On the basis of the
premise that the long half-life of the protein increases the potential
for oxidative damage, we investigated the effects of oxidation on
misfolding/aggregation of SOD1 and ALS-associated SOD1 mutants.
Zinc-deficient wild-type SOD1 and SOD1 mutants were extremely prone to
form visible aggregates upon oxidation as compared with wild-type
holo-protein. Oxidation of select histidine residues that bind metals
in the active site mediates SOD1 aggregation. Our results provide a
plausible model to explain the accumulation of SOD1 aggregates in motor
neurons affected in ALS.
Oxidation-induced Misfolding and Aggregation of
Superoxide Dismutase and Its Implications for Amyotrophic Lateral
Sclerosis*
,,
**,
Departments of Medical Biophysics and
Biochemistry, Ontario Cancer Institute, University of Toronto, Toronto,
Ontario M5G 2M9, Canada, § Caprion Pharmaceuticals, Inc.,
St. Laurent, Quebec H4S 2C8, Canada, ¶ Departments of
Anesthesiology, Pharmacology/Toxicology, and Biochemistry and Molecular
Genetics, University of Alabama, Birmingham, Alabama 35294, and
Centre for Research in Neurodegenerative Diseases and Sunnybrook
and Women's College Health Sciences Centre, University of
Toronto, Toronto, Ontario M5S 3H2, Canada
*
This work was supported by grants from Caprion
Pharmaceuticals Inc., Temerty Family Foundation (to N. R. C.), and
Canadian Institutes of Health Research (to A. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. E-mail:
chakrab@ uhnres.utoronto.ca.
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