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A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable whe...

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Autores principales: McAlary, L., Shephard, V.K., Wright, G.S.A., Yerbury, J.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8885447/
https://www.ncbi.nlm.nih.gov/pubmed/35065969
http://dx.doi.org/10.1016/j.jbc.2022.101612
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author McAlary, L.
Shephard, V.K.
Wright, G.S.A.
Yerbury, J.J.
author_facet McAlary, L.
Shephard, V.K.
Wright, G.S.A.
Yerbury, J.J.
author_sort McAlary, L.
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable when it contains its metal ligands and has formed its native intramolecular disulfide. Mutations in SOD1 reduce protein folding stability via disruption of metal binding and/or disulfide formation, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS; however, the results have been mixed. Here, we utilize a small-molecule polytherapy of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) and ebselen to mimic the metal delivery and disulfide bond promoting activity of the cellular chaperone of SOD1, the “copper chaperone for SOD1.” Using microscopy with automated image analysis, we find that polytherapy using CuATSM and ebselen is highly effective and acts in synergy to reduce inclusion formation in a cell model of SOD1 aggregation for multiple ALS-associated mutants. Polytherapy reduces mutant SOD1-associated cell death, as measured by live-cell microscopy. Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS.
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spelling pubmed-88854472022-03-04 A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis McAlary, L. Shephard, V.K. Wright, G.S.A. Yerbury, J.J. J Biol Chem Research Article Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable when it contains its metal ligands and has formed its native intramolecular disulfide. Mutations in SOD1 reduce protein folding stability via disruption of metal binding and/or disulfide formation, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS; however, the results have been mixed. Here, we utilize a small-molecule polytherapy of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) and ebselen to mimic the metal delivery and disulfide bond promoting activity of the cellular chaperone of SOD1, the “copper chaperone for SOD1.” Using microscopy with automated image analysis, we find that polytherapy using CuATSM and ebselen is highly effective and acts in synergy to reduce inclusion formation in a cell model of SOD1 aggregation for multiple ALS-associated mutants. Polytherapy reduces mutant SOD1-associated cell death, as measured by live-cell microscopy. Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS. American Society for Biochemistry and Molecular Biology 2022-01-20 /pmc/articles/PMC8885447/ /pubmed/35065969 http://dx.doi.org/10.1016/j.jbc.2022.101612 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
McAlary, L.
Shephard, V.K.
Wright, G.S.A.
Yerbury, J.J.
A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
title A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
title_full A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
title_fullStr A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
title_full_unstemmed A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
title_short A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
title_sort copper chaperone–mimetic polytherapy for sod1-associated amyotrophic lateral sclerosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8885447/
https://www.ncbi.nlm.nih.gov/pubmed/35065969
http://dx.doi.org/10.1016/j.jbc.2022.101612
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