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Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells
Copper (Cu) in its ionic forms is an essential element for mammals and its homeostasis is tightly controlled. Accordingly, Cu-dyshomeostasis can be lethal as is the case in the well-established genetic Wilson's and Menkes diseases. In Alzheimer's disease (AD), Cu-accumulation occurs in amy...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9580518/ https://www.ncbi.nlm.nih.gov/pubmed/36320914 http://dx.doi.org/10.1039/d2sc02593k |
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author | Okafor, Michael Gonzalez, Paulina Ronot, Pascale El Masoudi, Islah Boos, Anne Ory, Stéphane Chasserot-Golaz, Sylvette Gasman, Stéphane Raibaut, Laurent Hureau, Christelle Vitale, Nicolas Faller, Peter |
author_facet | Okafor, Michael Gonzalez, Paulina Ronot, Pascale El Masoudi, Islah Boos, Anne Ory, Stéphane Chasserot-Golaz, Sylvette Gasman, Stéphane Raibaut, Laurent Hureau, Christelle Vitale, Nicolas Faller, Peter |
author_sort | Okafor, Michael |
collection | PubMed |
description | Copper (Cu) in its ionic forms is an essential element for mammals and its homeostasis is tightly controlled. Accordingly, Cu-dyshomeostasis can be lethal as is the case in the well-established genetic Wilson's and Menkes diseases. In Alzheimer's disease (AD), Cu-accumulation occurs in amyloid plaques, where it is bound to the amyloid-beta peptide (Aβ). In vitro, Cu–Aβ is competent to catalyze the production of reactive oxygen species (ROS) in the presence of ascorbate under aerobic conditions, and hence Cu–Aβ is believed to contribute to the oxidative stress in AD. Several molecules that can recover extracellular Cu from Aβ and transport it back into cells with beneficial effects in cell culture and transgenic AD models were identified. However, all the Cu-shuttles currently available are not satisfactory due to various potential limitations including ion selectivity and toxicity. Hence, we designed a novel peptide-based Cu shuttle with the following properties: (i) it contains a Cu(ii)-binding motif that is very selective to Cu(ii) over all other essential metal ions; (ii) it is tagged with a fluorophore sensitive to Cu(ii)-binding and release; (iii) it is made of a peptide platform, which is very versatile to add new functions. The work presented here reports on the characterization of AKH-αR5W4(NBD), which is able to transport Cu ions selectively into PC12 cells and the imported Cu appeared bioavailable, likely via reductive release induced by glutathione. Moreover, AKH-αR5W4(NBD) was able to withdraw Cu from the Aβ(1–16) peptide and consequently inhibited the Cu-Aβ based reactive oxygen species production and related cell toxicity. Hence, AKH-αR5W4(NBD) could be a valuable new tool for Cu-transport into cells and suitable for mechanistic studies in cell culture, with potential applications in restoring Cu-homeostasis in Cu-related diseases such as AD. |
format | Online Article Text |
id | pubmed-9580518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-95805182022-10-31 Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells Okafor, Michael Gonzalez, Paulina Ronot, Pascale El Masoudi, Islah Boos, Anne Ory, Stéphane Chasserot-Golaz, Sylvette Gasman, Stéphane Raibaut, Laurent Hureau, Christelle Vitale, Nicolas Faller, Peter Chem Sci Chemistry Copper (Cu) in its ionic forms is an essential element for mammals and its homeostasis is tightly controlled. Accordingly, Cu-dyshomeostasis can be lethal as is the case in the well-established genetic Wilson's and Menkes diseases. In Alzheimer's disease (AD), Cu-accumulation occurs in amyloid plaques, where it is bound to the amyloid-beta peptide (Aβ). In vitro, Cu–Aβ is competent to catalyze the production of reactive oxygen species (ROS) in the presence of ascorbate under aerobic conditions, and hence Cu–Aβ is believed to contribute to the oxidative stress in AD. Several molecules that can recover extracellular Cu from Aβ and transport it back into cells with beneficial effects in cell culture and transgenic AD models were identified. However, all the Cu-shuttles currently available are not satisfactory due to various potential limitations including ion selectivity and toxicity. Hence, we designed a novel peptide-based Cu shuttle with the following properties: (i) it contains a Cu(ii)-binding motif that is very selective to Cu(ii) over all other essential metal ions; (ii) it is tagged with a fluorophore sensitive to Cu(ii)-binding and release; (iii) it is made of a peptide platform, which is very versatile to add new functions. The work presented here reports on the characterization of AKH-αR5W4(NBD), which is able to transport Cu ions selectively into PC12 cells and the imported Cu appeared bioavailable, likely via reductive release induced by glutathione. Moreover, AKH-αR5W4(NBD) was able to withdraw Cu from the Aβ(1–16) peptide and consequently inhibited the Cu-Aβ based reactive oxygen species production and related cell toxicity. Hence, AKH-αR5W4(NBD) could be a valuable new tool for Cu-transport into cells and suitable for mechanistic studies in cell culture, with potential applications in restoring Cu-homeostasis in Cu-related diseases such as AD. The Royal Society of Chemistry 2022-09-21 /pmc/articles/PMC9580518/ /pubmed/36320914 http://dx.doi.org/10.1039/d2sc02593k Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Okafor, Michael Gonzalez, Paulina Ronot, Pascale El Masoudi, Islah Boos, Anne Ory, Stéphane Chasserot-Golaz, Sylvette Gasman, Stéphane Raibaut, Laurent Hureau, Christelle Vitale, Nicolas Faller, Peter Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells |
title | Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells |
title_full | Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells |
title_fullStr | Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells |
title_full_unstemmed | Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells |
title_short | Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells |
title_sort | development of cu(ii)-specific peptide shuttles capable of preventing cu–amyloid beta toxicity and importing bioavailable cu into cells |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9580518/ https://www.ncbi.nlm.nih.gov/pubmed/36320914 http://dx.doi.org/10.1039/d2sc02593k |
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