title: Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis.
abstract: Mutations in copper/zinc superoxide dismutase (SOD1) cause a form of familial amyotrophic lateral sclerosis (ALS). The pathogenesis of familial ALS may be associated with aberrant copper chemistry through a cysteine residue in mutant SOD1. Ammonium tetrathiomolybdate (TTM) is a copper-chelating drug that is capable of removing a copper ion from copper-thiolate clusters, such as SOD1. We found that TTM exerted therapeutic benefits in a mouse model of familial ALS (SOD1(G93A)). TTM treatment significantly delayed disease onset, slowed disease progression and prolonged survival by approximately 20%, 42% and 25%, respectively. TTM also effectively depressed the spinal copper ion level and inhibited lipid peroxidation, with a significant suppression of SOD1 enzymatic activity in SOD1(G93A). These results support the hypothesis that aberrant copper chemistry through a cysteine residue plays a critical role in mutant SOD1 toxicity and that TTM may be a promising therapy for familial ALS with SOD1 mutants.
authors.affiliation: Research Unit of Clinical Pharmacy, College of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tokuda
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ono
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishige
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Watanabe
authors.forename: Eriko
authors.initials: E
authors.lastname: Okawa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000595:Amino Acid Sequence / Q000187:drug effects; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D003300:Copper / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008982:Molybdenum / Q000494:pharmacology* / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D003545:Cysteine