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 Hare, Philip 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 & 9 others 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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)8021-8031
Number of pages11
JournalJournal of Neuroscience
Volume34
Issue number23
DOIs
Publication statusPublished - 4 Jun 2014
Externally publishedYes

Cite this

Roberts, Blaine R. ; Lim, Nastasia K H ; McAllum, Erin J. ; Donnelly, Paul S. ; Hare, Dominic ; Doble, Philip ; Turner, Bradley J. ; Price, Katherine A ; Lim, Sin Chun ; Paterson, Brett M ; Hickey, James L. ; Rhoads, Timothy W ; Williams, Jared R ; Kanninen, Katja M. ; Hung, Lin W. ; Liddell, Jeffrey R. ; Grubman, Alexandra ; Monty, Jean-Francois ; Llanos, Roxana M ; Kramer, David R ; Mercer, Julian F B ; Bush, Ashley I. ; Masters, Colin L. ; Duce, James A. ; Li, Qiao Xin ; Beckman, Joseph S ; Barnham, Kevin J. ; White, Anthony R ; Crouch, Peter J. / 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. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 23. pp. 8021-8031.
@article{9c9cb1eee5d141eebbe812106674638f,
title = "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",
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.",
author = "Roberts, {Blaine R.} and Lim, {Nastasia K H} and McAllum, {Erin J.} and Donnelly, {Paul S.} and Dominic Hare and Philip Doble and Turner, {Bradley J.} and Price, {Katherine A} and Lim, {Sin Chun} and Paterson, {Brett M} and Hickey, {James L.} and Rhoads, {Timothy W} and Williams, {Jared R} and Kanninen, {Katja M.} and Hung, {Lin W.} and Liddell, {Jeffrey R.} and Alexandra Grubman and Jean-Francois Monty and Llanos, {Roxana M} and Kramer, {David R} and Mercer, {Julian F B} and Bush, {Ashley I.} and Masters, {Colin L.} and Duce, {James A.} and Li, {Qiao Xin} and Beckman, {Joseph S} and Barnham, {Kevin J.} and White, {Anthony R} and Crouch, {Peter J.}",
year = "2014",
month = "6",
day = "4",
doi = "10.1523/JNEUROSCI.4196-13.2014",
language = "English",
volume = "34",
pages = "8021--8031",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "23",

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Roberts, BR, Lim, NKH, McAllum, EJ, Donnelly, PS, Hare, D, Doble, P, Turner, BJ, Price, KA, Lim, SC, Paterson, BM, Hickey, JL, Rhoads, TW, Williams, JR, Kanninen, KM, Hung, LW, Liddell, JR, Grubman, A, Monty, J-F, Llanos, RM, Kramer, DR, Mercer, JFB, Bush, AI, Masters, CL, Duce, JA, Li, QX, Beckman, JS, Barnham, KJ, White, AR & Crouch, PJ 2014, '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' Journal of Neuroscience, vol. 34, no. 23, pp. 8021-8031. https://doi.org/10.1523/JNEUROSCI.4196-13.2014

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. / Roberts, Blaine R.; Lim, Nastasia K H; McAllum, Erin J.; Donnelly, Paul S.; Hare, Dominic; Doble, Philip; Turner, Bradley J.; Price, Katherine A; Lim, Sin Chun; Paterson, Brett M; Hickey, James L.; Rhoads, Timothy W; Williams, Jared R; Kanninen, Katja M.; Hung, Lin W.; Liddell, Jeffrey R.; Grubman, Alexandra; Monty, Jean-Francois; Llanos, Roxana M; Kramer, David R; Mercer, Julian F B; Bush, Ashley I.; Masters, Colin L.; Duce, James A.; Li, Qiao Xin; Beckman, Joseph S; Barnham, Kevin J.; White, Anthony R; Crouch, Peter J.

In: Journal of Neuroscience, Vol. 34, No. 23, 04.06.2014, p. 8021-8031.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Roberts, Blaine R.

AU - Lim, Nastasia K H

AU - McAllum, Erin J.

AU - Donnelly, Paul S.

AU - Hare, Dominic

AU - Doble, Philip

AU - Turner, Bradley J.

AU - Price, Katherine A

AU - Lim, Sin Chun

AU - Paterson, Brett M

AU - Hickey, James L.

AU - Rhoads, Timothy W

AU - Williams, Jared R

AU - Kanninen, Katja M.

AU - Hung, Lin W.

AU - Liddell, Jeffrey R.

AU - Grubman, Alexandra

AU - Monty, Jean-Francois

AU - Llanos, Roxana M

AU - Kramer, David R

AU - Mercer, Julian F B

AU - Bush, Ashley I.

AU - Masters, Colin L.

AU - Duce, James A.

AU - Li, Qiao Xin

AU - Beckman, Joseph S

AU - Barnham, Kevin J.

AU - White, Anthony R

AU - Crouch, Peter J.

PY - 2014/6/4

Y1 - 2014/6/4

N2 - 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.

AB - 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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U2 - 10.1523/JNEUROSCI.4196-13.2014

DO - 10.1523/JNEUROSCI.4196-13.2014

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SP - 8021

EP - 8031

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

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