ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism

Erin J McAllum, Blaine R. Roberts, James L. Hickey, Theresa N. Dang, Alexandra Grubman, Paul S. Donnelly, Jeffrey R. Liddell, Anthony R White, Peter J. Crouch

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Mutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zincII [ZnII(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the ZnII(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of ZnII(atsm) in the presence of Cu to form the Cu-analogue CuII(atsm), indicating that the observed therapeutic effects for ZnII(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu.
Original languageEnglish
Pages (from-to)20-24
Number of pages5
JournalNeurobiology of Disease
Volume81
DOIs
Publication statusPublished - 1 Sep 2015
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Bisthiosemicarbazone (btsc)
  • Copper
  • Copper/zinc-superoxide dismutase (SOD1)
  • Inductively coupled plasma mass spectrometry (ICP-MS)
  • Metal
  • Mouse model
  • Therapeutic
  • Transmetallation
  • Zinc

Cite this

McAllum, E. J., Roberts, B. R., Hickey, J. L., Dang, T. N., Grubman, A., Donnelly, P. S., ... Crouch, P. J. (2015). ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism. Neurobiology of Disease, 81, 20-24. https://doi.org/10.1016/j.nbd.2015.02.023
McAllum, Erin J ; Roberts, Blaine R. ; Hickey, James L. ; Dang, Theresa N. ; Grubman, Alexandra ; Donnelly, Paul S. ; Liddell, Jeffrey R. ; White, Anthony R ; Crouch, Peter J. / ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism. In: Neurobiology of Disease. 2015 ; Vol. 81. pp. 20-24.
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abstract = "Mutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20{\%} of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zincII [ZnII(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the ZnII(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of ZnII(atsm) in the presence of Cu to form the Cu-analogue CuII(atsm), indicating that the observed therapeutic effects for ZnII(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu.",
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McAllum, EJ, Roberts, BR, Hickey, JL, Dang, TN, Grubman, A, Donnelly, PS, Liddell, JR, White, AR & Crouch, PJ 2015, 'ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism' Neurobiology of Disease, vol. 81, pp. 20-24. https://doi.org/10.1016/j.nbd.2015.02.023

ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism. / McAllum, Erin J; Roberts, Blaine R.; Hickey, James L.; Dang, Theresa N.; Grubman, Alexandra; Donnelly, Paul S.; Liddell, Jeffrey R.; White, Anthony R; Crouch, Peter J.

In: Neurobiology of Disease, Vol. 81, 01.09.2015, p. 20-24.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ZnII(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism

AU - McAllum, Erin J

AU - Roberts, Blaine R.

AU - Hickey, James L.

AU - Dang, Theresa N.

AU - Grubman, Alexandra

AU - Donnelly, Paul S.

AU - Liddell, Jeffrey R.

AU - White, Anthony R

AU - Crouch, Peter J.

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Y1 - 2015/9/1

N2 - Mutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zincII [ZnII(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the ZnII(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of ZnII(atsm) in the presence of Cu to form the Cu-analogue CuII(atsm), indicating that the observed therapeutic effects for ZnII(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu.

AB - Mutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zincII [ZnII(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the ZnII(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of ZnII(atsm) in the presence of Cu to form the Cu-analogue CuII(atsm), indicating that the observed therapeutic effects for ZnII(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu.

KW - Amyotrophic lateral sclerosis (ALS)

KW - Bisthiosemicarbazone (btsc)

KW - Copper

KW - Copper/zinc-superoxide dismutase (SOD1)

KW - Inductively coupled plasma mass spectrometry (ICP-MS)

KW - Metal

KW - Mouse model

KW - Therapeutic

KW - Transmetallation

KW - Zinc

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EP - 24

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

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