title: Dysregulation of intracellular copper trafficking pathway in a mouse model of mutant copper/zinc superoxide dismutase-linked familial amyotrophic lateral sclerosis.
abstract: Mutations in copper/zinc superoxide dismutase (SOD1) are responsible for 20% of familial amyotrophic lateral sclerosis through a gain-of-toxic function. We have recently shown that ammonium tetrathiomolybdate, an intracellular copper-chelating reagent, has an excellent therapeutic benefit in a mouse model for amyotrophic lateral sclerosis. This finding suggests that mutant SOD1 might disrupt intracellular copper homeostasis. In this study, we investigated the effects of mutant SOD1 on the components of the copper trafficking pathway, which regulate intracellular copper homeostasis. We found that mutant, but not wild-type, SOD1 shifts intracellular copper homeostasis toward copper accumulation in the spinal cord during disease progression: copper influx increases, copper chaperones are up-regulated, and copper efflux decreases. This dysregulation was observed within spinal motor neurons and was proportionally associated with an age-dependent increase in spinal copper ion levels. We also found that a subset of the copper trafficking pathway constituents co-aggregated with mutant SOD1. These results indicate that the nature of mutant SOD1 toxicity might involve the dysregulation of the copper trafficking pathway, resulting in the disruption of intracellular copper homeostasis.
authors: Research Unit of Clinical Pharmacy, College of Pharmacy, Nihon University, Tokyo, Japan.
authors: Eiichi
authors: E
authors: Tokuda
authors: Eriko
authors: E
authors: Okawa
authors: Shin-Ichi
authors: S
authors: Ono
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D027682:Cation Transport Proteins / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: C499247:Atox1 protein, mouse; C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; C491962:Ccs protein, mouse; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D008565:Membrane Proteins; D018832:Molecular Chaperones; C490077:Slc31a1 protein, mouse; D003300:Copper; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases