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Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord
Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304223/ https://www.ncbi.nlm.nih.gov/pubmed/28205575 http://dx.doi.org/10.1038/srep42292 |
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author | Hilton, James B. Mercer, Stephen W. Lim, Nastasia K. H. Faux, Noel G. Buncic, Gojko Beckman, Joseph S. Roberts, Blaine R. Donnelly, Paul S. White, Anthony R. Crouch, Peter J. |
author_facet | Hilton, James B. Mercer, Stephen W. Lim, Nastasia K. H. Faux, Noel G. Buncic, Gojko Beckman, Joseph S. Roberts, Blaine R. Donnelly, Paul S. White, Anthony R. Crouch, Peter J. |
author_sort | Hilton, James B. |
collection | PubMed |
description | Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex Cu(II)(atsm) tested for therapeutic efficacy in mice expressing SOD1(G93A) on a mixed genetic background. Oral administration of Cu(II)(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1(G93A) mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the Cu(II)(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with Cu(II)(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for Cu(II)(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1. |
format | Online Article Text |
id | pubmed-5304223 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53042232017-03-14 Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord Hilton, James B. Mercer, Stephen W. Lim, Nastasia K. H. Faux, Noel G. Buncic, Gojko Beckman, Joseph S. Roberts, Blaine R. Donnelly, Paul S. White, Anthony R. Crouch, Peter J. Sci Rep Article Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex Cu(II)(atsm) tested for therapeutic efficacy in mice expressing SOD1(G93A) on a mixed genetic background. Oral administration of Cu(II)(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1(G93A) mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the Cu(II)(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with Cu(II)(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for Cu(II)(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1. Nature Publishing Group 2017-02-13 /pmc/articles/PMC5304223/ /pubmed/28205575 http://dx.doi.org/10.1038/srep42292 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Hilton, James B. Mercer, Stephen W. Lim, Nastasia K. H. Faux, Noel G. Buncic, Gojko Beckman, Joseph S. Roberts, Blaine R. Donnelly, Paul S. White, Anthony R. Crouch, Peter J. Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord |
title | Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord |
title_full | Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord |
title_fullStr | Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord |
title_full_unstemmed | Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord |
title_short | Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord |
title_sort | cu(ii)(atsm) improves the neurological phenotype and survival of sod1(g93a) mice and selectively increases enzymatically active sod1 in the spinal cord |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304223/ https://www.ncbi.nlm.nih.gov/pubmed/28205575 http://dx.doi.org/10.1038/srep42292 |
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