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NEUROLOGY 1996;47:36S-39S
© 1996 American Academy of Neurology

Cell death mechanisms in ALS

D. E. Bredesen, MD, M. Wiedau-Pazos, MD, PhD, J. J. Goto, BS, S. Rabizadeh, BS, J. A. Roe, PhD, E. B. Gralla, PhD, L. M. Ellerby, PhD and J. S. Valentine, PhD

From the Program on Aging (Dr. Bredesen, S. Rabizadeh, and Dr. Ellerby), The Burnham Institute, La Jolla, CA; and the Department of Chemistry and Biochemistry (Dr. Wiedau-Pazos, J.J. Goto, and Drs. Gralla and Valentine), University of California, Los Angeles, CA.
Supported by NIH grants AG12282 (D.E.B.), GM28222 (J.S.V.), and DK46828 (J.S.V.), and grants from the Amyotrophic Lateral Sclerosis Association (E.B.G., L.M.E.) and the VivoRx Corporation (S.R.).
Address correspondence and reprint requests to Dr. D. Bredesen, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037.

Abstract.

Mutations in copper-zinc superoxide dismutase (CuZnSOD) that are associated with familial ALS (FALS) are dominant, gain-of-function mutations, but the nature of the function gained has not been identified. In addition to catalyzing the dismutation of superoxide, copper-zinc superoxide dismutase also displays peroxidase activity. Whereas mutants A4V and G93A retained superoxide dismutase activity, they demonstrated a markedly enhanced copper-dependent peroxidase activity in comparison with that of the wild type enzyme as detected by the spin trap 5,5 prime-dimethyl-1-pyrroline N-oxide (DMPO) in electron paramagnetic resonance measurements. Two copper chelators, diethyldithiocarbamate and penicillamine, inhibited the mutants' peroxidase activity, but not that of the wild type enzyme, at stoichiometric concentrations; furthermore, these copper chelators enhanced neural survival in a cell-culture model of ALS but did not alter survival of cells expressing only wild type copper-zinc superoxide dismutase. These observations suggest that oxidative reactions catalyzed by mutant copper-zinc superoxide dismutases may initiate the neuropathologic changes of FALS.

NEUROLOGY 1996;47(Suppl 2): S36-S39






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