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Articles, Neurobiology of Disease

Oral Treatment with CuII(atsm) Increases Mutant SOD1 In Vivo but Protects Motor Neurons and Improves the Phenotype of a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Blaine R. Roberts, Nastasia K. H. Lim, Erin J. McAllum, Paul S. Donnelly, Dominic J. Hare, Philip A. Doble, Bradley J. Turner, Katherine A. Price, Sin Chun Lim, Brett M. Paterson, James L. Hickey, Timothy W. Rhoads, Jared R. Williams, Katja M. Kanninen, Lin W. Hung, Jeffrey R. Liddell, Alexandra Grubman, Jean-Francois Monty, Roxana M. Llanos, David R. Kramer, Julian F. B. Mercer, Ashley I. Bush, Colin L. Masters, James A. Duce, Qiao-Xin Li, Joseph S. Beckman, Kevin J. Barnham, Anthony R. White and Peter J. Crouch
Journal of Neuroscience 4 June 2014, 34 (23) 8021-8031; DOI: https://doi.org/10.1523/JNEUROSCI.4196-13.2014
Blaine R. Roberts
1Florey Institute of Neuroscience and Mental Health,
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Nastasia K. H. Lim
2Department of Pathology,
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Erin J. McAllum
2Department of Pathology,
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Paul S. Donnelly
3School of Chemistry,
4Bio21 Institute of Biotechnology and Molecular Biology, and
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Dominic J. Hare
1Florey Institute of Neuroscience and Mental Health,
6Elemental Bio-imaging Facility, and Department of Chemistry and Forensic Science, University of Technology Sydney, 2007 Broadway, New South Wales, Australia,
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Philip A. Doble
6Elemental Bio-imaging Facility, and Department of Chemistry and Forensic Science, University of Technology Sydney, 2007 Broadway, New South Wales, Australia,
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Bradley J. Turner
1Florey Institute of Neuroscience and Mental Health,
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Katherine A. Price
2Department of Pathology,
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Sin Chun Lim
3School of Chemistry,
4Bio21 Institute of Biotechnology and Molecular Biology, and
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Brett M. Paterson
3School of Chemistry,
4Bio21 Institute of Biotechnology and Molecular Biology, and
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James L. Hickey
3School of Chemistry,
4Bio21 Institute of Biotechnology and Molecular Biology, and
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Timothy W. Rhoads
7Department of Biochemistry and Biophysics,
8Linus Pauling Institute, and
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Jared R. Williams
7Department of Biochemistry and Biophysics,
8Linus Pauling Institute, and
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Katja M. Kanninen
2Department of Pathology,
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Lin W. Hung
1Florey Institute of Neuroscience and Mental Health,
4Bio21 Institute of Biotechnology and Molecular Biology, and
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Jeffrey R. Liddell
2Department of Pathology,
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Alexandra Grubman
2Department of Pathology,
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Jean-Francois Monty
10Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, 3125 Victoria, Australia,
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Roxana M. Llanos
10Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, 3125 Victoria, Australia,
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David R. Kramer
11ANU Medical School, ANU College of Medicine, Biology and the Environment, The Australian National University, 0200 Canberra, Australian Capital Territory, Australia, and
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Julian F. B. Mercer
10Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, 3125 Victoria, Australia,
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Ashley I. Bush
1Florey Institute of Neuroscience and Mental Health,
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Colin L. Masters
1Florey Institute of Neuroscience and Mental Health,
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James A. Duce
1Florey Institute of Neuroscience and Mental Health,
12School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
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Qiao-Xin Li
1Florey Institute of Neuroscience and Mental Health,
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Joseph S. Beckman
7Department of Biochemistry and Biophysics,
8Linus Pauling Institute, and
9Environmental Health Sciences Centre, Oregon State University, Corvallis, Oregon 97331,
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Kevin J. Barnham
1Florey Institute of Neuroscience and Mental Health,
4Bio21 Institute of Biotechnology and Molecular Biology, and
5Department of Pharmacology, The University of Melbourne, Parkville, 3010 Victoria, Australia,
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Anthony R. White
1Florey Institute of Neuroscience and Mental Health,
2Department of Pathology,
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Peter J. Crouch
1Florey Institute of Neuroscience and Mental Health,
2Department of Pathology,
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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)copperII [CuII(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 CuII(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched 65CuII(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from CuII(atsm) to SOD1, suggesting the improved locomotor function and survival of the CuII(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 CuII(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.

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The Journal of Neuroscience: 34 (23)
Journal of Neuroscience
Vol. 34, Issue 23
4 Jun 2014
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Oral Treatment with CuII(atsm) Increases Mutant SOD1 In Vivo but Protects Motor Neurons and Improves the Phenotype of a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis
Blaine R. Roberts, Nastasia K. H. Lim, Erin J. McAllum, Paul S. Donnelly, Dominic J. Hare, Philip A. Doble, Bradley J. Turner, Katherine A. Price, Sin Chun Lim, Brett M. Paterson, James L. Hickey, Timothy W. Rhoads, Jared R. Williams, Katja M. Kanninen, Lin W. Hung, Jeffrey R. Liddell, Alexandra Grubman, Jean-Francois Monty, Roxana M. Llanos, David R. Kramer, Julian F. B. Mercer, Ashley I. Bush, Colin L. Masters, James A. Duce, Qiao-Xin Li, Joseph S. Beckman, Kevin J. Barnham, Anthony R. White, Peter J. Crouch
Journal of Neuroscience 4 June 2014, 34 (23) 8021-8031; DOI: 10.1523/JNEUROSCI.4196-13.2014

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Oral Treatment with CuII(atsm) Increases Mutant SOD1 In Vivo but Protects Motor Neurons and Improves the Phenotype of a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis
Blaine R. Roberts, Nastasia K. H. Lim, Erin J. McAllum, Paul S. Donnelly, Dominic J. Hare, Philip A. Doble, Bradley J. Turner, Katherine A. Price, Sin Chun Lim, Brett M. Paterson, James L. Hickey, Timothy W. Rhoads, Jared R. Williams, Katja M. Kanninen, Lin W. Hung, Jeffrey R. Liddell, Alexandra Grubman, Jean-Francois Monty, Roxana M. Llanos, David R. Kramer, Julian F. B. Mercer, Ashley I. Bush, Colin L. Masters, James A. Duce, Qiao-Xin Li, Joseph S. Beckman, Kevin J. Barnham, Anthony R. White, Peter J. Crouch
Journal of Neuroscience 4 June 2014, 34 (23) 8021-8031; DOI: 10.1523/JNEUROSCI.4196-13.2014
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