title: Metal-deficient SOD1 in amyotrophic lateral sclerosis.
abstract: Mutations to the ubiquitous antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) were the first established genetic cause of the fatal, adult-onset neurodegenerative disease amyotrophic lateral sclerosis (ALS). It is widely accepted that these mutations do not cause ALS via a loss of antioxidant function, but elucidating the alternate toxic gain of function has proven to be elusive. Under physiological conditions, SOD1 binds one copper ion and one zinc ion per monomer to form a highly stable and functional homodimer, but there is now ample evidence to indicate aberrant persistence of SOD1 in an intermediate metal-deficient state may contribute to the protein's involvement in ALS. This review briefly discusses some of the data to support a role for metal-deficient SOD1 in the development of ALS and some of the outcomes from drug development studies that have aimed to modify the symptoms of ALS by targeting the metal state of SOD1. The implications for the metal state of SOD1 in cases of sporadic ALS that do not involve mutant SOD1 are also discussed.
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: James B
authors.initials: JB
authors.lastname: Hilton
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D003300:Copper / Q000172:deficiency; D004195:Disease Models, Animal; D006801:Humans; D008670:Metals / Q000378:metabolism*; D066329:Protein Aggregates; D012377:Rodentia; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015032:Zinc / Q000172:deficiency
chemical_list: D008670:Metals; D066329:Protein Aggregates; C000606290:SOD1 protein, human; D003300:Copper; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc