title: CuII(atsm) improves the neurological phenotype and survival of SOD1G93Amice and selectively increases enzymatically active SOD1 in the spinal cord.
abstract: Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex CuII(atsm) tested for therapeutic efficacy in mice expressing SOD1G93Aon a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1G93Amice is instigated by expression of the mutant SOD1, we show the improved phenotype of the CuII(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with CuII(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for CuII(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.
authors.affiliation: Department of Pathology, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: James B
authors.initials: JB
authors.lastname: Hilton
authors.affiliation: Department of Pathology, the University of Melbourne, Parkville, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Mercer
authors.affiliation: Department of Pathology, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Nastasia K H
authors.initials: NK
authors.lastname: Lim
authors.affiliation: Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, Victoria, Australia.|Cooperative Research Centre for Mental Health, Parkville, Victoria, Australia.
authors.forename: Noel G
authors.initials: NG
authors.lastname: Faux
authors.affiliation: School of Chemistry, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gojko
authors.initials: G
authors.lastname: Buncic
authors.affiliation: Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
authors.affiliation: Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Blaine R
authors.initials: BR
authors.lastname: Roberts
authors.affiliation: School of Chemistry, the University of Melbourne, Parkville, Victoria, Australia.|Bio21 Molecular Science and Biotechnology Institute, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: Department of Pathology, the University of Melbourne, Parkville, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.affiliation: Department of Pathology, the University of Melbourne, Parkville, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
mesh_terms: D000284:Administration, Oral; D000818:Animals; D056831:Coordination Complexes; D003300:Copper / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000378:metabolism*; D016019:Survival Analysis; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000494:pharmacology*; D014020:Tissue Extracts
chemical_list: D056831:Coordination Complexes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; D014020:Tissue Extracts; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D003300:Copper; D045304:Cytochromes c; D013482:Superoxide Dismutase