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