Abstract
Mutations in copper, zinc superoxide dismutase (SOD) have been implicated in the selective death of motor neurons in 2 percent of amyotrophic lateral sclerosis (ALS) patients. The loss of zinc from either wild-type or ALS-mutant SODs was sufficient to induce apoptosis in cultured motor neurons. Toxicity required that copper be bound to SOD and depended on endogenous production of nitric oxide. When replete with zinc, neither ALS-mutant nor wild-type copper, zinc SODs were toxic, and both protected motor neurons from trophic factor withdrawal. Thus, zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide.
Publication types
- Comment
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Amyotrophic Lateral Sclerosis / drug therapy
- Amyotrophic Lateral Sclerosis / enzymology*
- Amyotrophic Lateral Sclerosis / genetics
- Amyotrophic Lateral Sclerosis / pathology
- Animals
- Apoptosis*
- Brain-Derived Neurotrophic Factor / pharmacology
- Cells, Cultured
- Chelating Agents / pharmacology
- Copper / metabolism
- Fluoresceins / metabolism
- Liposomes
- Motor Neurons / cytology*
- Motor Neurons / metabolism
- Mutation
- Nitrates / metabolism
- Nitric Oxide / metabolism*
- Nitric Oxide Synthase / antagonists & inhibitors
- Nitric Oxide Synthase / metabolism
- Nitric Oxide Synthase Type I
- Oxidation-Reduction
- Rats
- Superoxide Dismutase / chemistry
- Superoxide Dismutase / genetics
- Superoxide Dismutase / metabolism*
- Superoxide Dismutase / toxicity
- Superoxides / metabolism
- Zinc / metabolism*
Substances
- Brain-Derived Neurotrophic Factor
- Chelating Agents
- Fluoresceins
- Liposomes
- Nitrates
- 2',7'-dichlorodihydrofluorescein
- Superoxides
- peroxynitric acid
- Nitric Oxide
- Copper
- Nitric Oxide Synthase
- Nitric Oxide Synthase Type I
- Nos1 protein, rat
- Superoxide Dismutase
- Zinc