title: Longitudinal assessment of metal concentrations and copper isotope ratios in the G93A SOD1 mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, which involves progressive motor neuron degeneration in the central nervous system (CNS). The G93A SOD1 mouse model simulates one of the most common causes of familial ALS through the overexpression of a mutated form of the human gene encoding copper/zinc superoxide dismutase (SOD1). Transition metals, particularly Cu and Zn, have been shown to behave abnormally in the disease context and have been hypothesized to contribute to and potentially trigger the disease. In this study, concentrations of Cu, Zn and Fe, as well as Cu isotope ratios were assessed in keystone tissues of ALS, including the brain, spinal cord, muscle and whole blood, from transgenic mutant SOD1G93Amice and non-transgenic controls. While no consistent Cu isotope signal was found to be related to the disease state, concentrations of Cu, Zn and Fe were significantly elevated in muscle tissue of the transgenic mice, even at pre-symptomatic time points. In brain and muscle tissue, in both animal groups, a time-dependent Cu isotope signal was observed. We hypothesize that the early and significant elevation in metal concentration in muscle tissue from SOD1 transgenic mice could facilitate the development of ALS, without affecting the overall signal from well-buffered CNS tissues. Ageing may be recorded isotopically as a shift from a neonatal Cu pool as inherited from the mother, through dietary Cu and recycling processes.
authors.affiliation: Wollongong Isotope Geochronology Laboratory, School of Earth and Environmental Sciences, University of Wollongong, Wollongong, NSW 2522, Australia. tge571@uowmail.edu.au.
authors.forename: T Gabriel
authors.identifier: 0000-0001-9381-6495
authors.initials: TG
authors.lastname: Enge
authors.affiliation: Illawarra Health and Medical Research Institute and School of Biological Sciences, University of Wollongong, Australia.
authors.forename: Heath
authors.initials: H
authors.lastname: Ecroyd
authors.affiliation: Center for Medical and Molecular Bioscience and School of Chemistry, University of Wollongong, Australia.
authors.forename: Dianne F
authors.initials: DF
authors.lastname: Jolley
authors.affiliation: Illawarra Health and Medical Research Institute and School of Biological Sciences, University of Wollongong, Australia.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Yerbury
authors.affiliation: Wollongong Isotope Geochronology Laboratory, School of Earth and Environmental Sciences, University of Wollongong, Wollongong, NSW 2522, Australia. tge571@uowmail.edu.au.
authors.forename: Anthony
authors.identifier: 0000-0002-3575-0106
authors.initials: A
authors.lastname: Dosseto
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D003301:Copper Radioisotopes / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008670:Metals / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000072105:Superoxide Dismutase-1 / Q000502:physiology*
chemical_list: D003301:Copper Radioisotopes; D008670:Metals; D000072105:Superoxide Dismutase-1