Cell death mechanisms in ALS.
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'-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.
Bredesen
D E
DE
Program on Aging, Burnham Institute, La Jolla, CA 92037, USA.
Wiedau-Pazos
M
M
Goto
J J
JJ
Rabizadeh
S
S
Roe
J A
JA
Gralla
E B
EB
Ellerby
L M
LM
Valentine
J S
JS
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D016923:Cell Death; D006801:Humans; D013482:Superoxide Dismutase / Q000378:metabolism
D013482:Superoxide Dismutase