Oral treatment with Cu<sup>II</sup>(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis
Roberts, BR
Lim, NKH
McAllum, EJ
Donnelly, PS
Hare, DJ
Doble, PA
Turner, BJ
Price, KA
Lim, SC
Paterson, BM
Hickey, JL
Rhoads, TW
Williams, JR
Kanninen, KM
Hung, LW
Liddell, JR
Grubman, A
Monty, JF
Llanos, RM
Kramer, DR
Mercer, JFB
Bush, AI
Masters, CL
Duce, JA
Li, QX
Beckman, JS
Barnham, KJ
White, AR
Crouch, PJ
- Publication Type:
- Journal Article
- Citation:
- Journal of Neuroscience, 2014, 34 (23), pp. 8021 - 8031
- Issue Date:
- 2014-01-01
Closed Access
Filename | Description | Size | |||
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2013006573OK.pdf | 2.89 MB |
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Roberts, BR | en_US |
dc.contributor.author | Lim, NKH | en_US |
dc.contributor.author | McAllum, EJ | en_US |
dc.contributor.author | Donnelly, PS | en_US |
dc.contributor.author |
Hare, DJ https://orcid.org/0000-0002-5922-7643 |
en_US |
dc.contributor.author |
Doble, PA https://orcid.org/0000-0002-8472-1301 |
en_US |
dc.contributor.author | Turner, BJ | en_US |
dc.contributor.author | Price, KA | en_US |
dc.contributor.author | Lim, SC | en_US |
dc.contributor.author | Paterson, BM | en_US |
dc.contributor.author | Hickey, JL | en_US |
dc.contributor.author | Rhoads, TW | en_US |
dc.contributor.author | Williams, JR | en_US |
dc.contributor.author | Kanninen, KM | en_US |
dc.contributor.author | Hung, LW | en_US |
dc.contributor.author | Liddell, JR | en_US |
dc.contributor.author | Grubman, A | en_US |
dc.contributor.author | Monty, JF | en_US |
dc.contributor.author | Llanos, RM | en_US |
dc.contributor.author | Kramer, DR | en_US |
dc.contributor.author | Mercer, JFB | en_US |
dc.contributor.author | Bush, AI | en_US |
dc.contributor.author | Masters, CL | en_US |
dc.contributor.author | Duce, JA | en_US |
dc.contributor.author | Li, QX | en_US |
dc.contributor.author | Beckman, JS | en_US |
dc.contributor.author | Barnham, KJ | en_US |
dc.contributor.author | White, AR | en_US |
dc.contributor.author | Crouch, PJ | en_US |
dc.date.issued | 2014-01-01 | en_US |
dc.identifier.citation | Journal of Neuroscience, 2014, 34 (23), pp. 8021 - 8031 | en_US |
dc.identifier.issn | 0270-6474 | en_US |
dc.identifier.uri | http://hdl.handle.net/10453/32805 | |
dc.identifier.uri | http://hdl.handle.net/10453/29629 | |
dc.description.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. © 2014 the authors. | en_US |
dc.relation.ispartof | Journal of Neuroscience | en_US |
dc.relation.isbasedon | 10.1523/JNEUROSCI.4196-13.2014 | en_US |
dc.subject.classification | Neurology & Neurosurgery | en_US |
dc.subject.mesh | Spinal Cord | en_US |
dc.subject.mesh | Motor Neurons | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Mice, Transgenic | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Amyotrophic Lateral Sclerosis | en_US |
dc.subject.mesh | Disease Models, Animal | en_US |
dc.subject.mesh | Organometallic Compounds | en_US |
dc.subject.mesh | Thiosemicarbazones | en_US |
dc.subject.mesh | Superoxide Dismutase | en_US |
dc.subject.mesh | Locomotion | en_US |
dc.subject.mesh | Phenotype | en_US |
dc.subject.mesh | Mutation | en_US |
dc.subject.mesh | Superoxide Dismutase-1 | en_US |
dc.subject.mesh | Administration, Oral | en_US |
dc.subject.mesh | Age Factors | en_US |
dc.subject.mesh | Cation Transport Proteins | en_US |
dc.subject.mesh | Chromatography, Gel | en_US |
dc.subject.mesh | Copper Transporter 1 | en_US |
dc.title | Oral treatment with Cu<sup>II</sup>(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis | en_US |
dc.type | Journal Article | |
utslib.citation.volume | 23 | en_US |
utslib.citation.volume | 34 | en_US |
utslib.for | 1109 Neurosciences | en_US |
utslib.for | 0301 Analytical Chemistry | en_US |
utslib.for | 1103 Clinical Sciences | en_US |
pubs.embargo.period | Not known | en_US |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences | |
pubs.organisational-group | /University of Technology Sydney/Strength - CFS - Centre for Forensic Science | |
utslib.copyright.status | closed_access | |
pubs.issue | 23 | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 34 | en_US |
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. © 2014 the authors.
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