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J Neurosci. 2014 Jun 4;34(23):8021-31. doi: 10.1523/JNEUROSCI.4196-13.2014.

Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis.

Author information

  • 1Florey Institute of Neuroscience and Mental Health.
  • 2Department of Pathology.
  • 3School of Chemistry, Bio21 Institute of Biotechnology and Molecular Biology, and.
  • 4Florey Institute of Neuroscience and Mental Health, Elemental Bio-imaging Facility, and Department of Chemistry and Forensic Science, University of Technology Sydney, 2007 Broadway, New South Wales, Australia.
  • 5Elemental Bio-imaging Facility, and Department of Chemistry and Forensic Science, University of Technology Sydney, 2007 Broadway, New South Wales, Australia.
  • 6Department of Biochemistry and Biophysics, Linus Pauling Institute, and.
  • 7Florey Institute of Neuroscience and Mental Health, Bio21 Institute of Biotechnology and Molecular Biology, and.
  • 8Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, 3125 Victoria, Australia.
  • 9ANU Medical School, ANU College of Medicine, Biology and the Environment, The Australian National University, 0200 Canberra, Australian Capital Territory, Australia, and.
  • 10Florey Institute of Neuroscience and Mental Health, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
  • 11Department of Biochemistry and Biophysics, Linus Pauling Institute, and Environmental Health Sciences Centre, Oregon State University, Corvallis, Oregon 97331.
  • 12Florey Institute of Neuroscience and Mental Health, Bio21 Institute of Biotechnology and Molecular Biology, and Department of Pharmacology, The University of Melbourne, Parkville, 3010 Victoria, Australia.
  • 13Florey Institute of Neuroscience and Mental Health, Department of Pathology.
  • 14Florey Institute of Neuroscience and Mental Health, Department of Pathology, pjcrouch@unimelb.edu.au.

Abstract

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu(II)(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched (65)Cu(II)(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu(II)(atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu(II)(atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu(II)(atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.

PMID:
24899723
DOI:
10.1523/JNEUROSCI.4196-13.2014
[PubMed - indexed for MEDLINE]
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