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Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain

Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whe...

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Autores principales: Washington-Hughes, Clorissa L., Roy, Shubhrajit, Seneviratne, Herana Kamal, Karuppagounder, Senthilkumar S., Morel, Yulemni, Jones, Jace W., Zak, Alex, Xiao, Tong, Boronina, Tatiana N., Cole, Robert N., Bumpus, Namandjé N., Chang, Christopher J., Dawson, Ted M., Lutsenko, Svetlana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870141/
https://www.ncbi.nlm.nih.gov/pubmed/36626371
http://dx.doi.org/10.1371/journal.pgen.1010558
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author Washington-Hughes, Clorissa L.
Roy, Shubhrajit
Seneviratne, Herana Kamal
Karuppagounder, Senthilkumar S.
Morel, Yulemni
Jones, Jace W.
Zak, Alex
Xiao, Tong
Boronina, Tatiana N.
Cole, Robert N.
Bumpus, Namandjé N.
Chang, Christopher J.
Dawson, Ted M.
Lutsenko, Svetlana
author_facet Washington-Hughes, Clorissa L.
Roy, Shubhrajit
Seneviratne, Herana Kamal
Karuppagounder, Senthilkumar S.
Morel, Yulemni
Jones, Jace W.
Zak, Alex
Xiao, Tong
Boronina, Tatiana N.
Cole, Robert N.
Bumpus, Namandjé N.
Chang, Christopher J.
Dawson, Ted M.
Lutsenko, Svetlana
author_sort Washington-Hughes, Clorissa L.
collection PubMed
description Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl’ cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.
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spelling pubmed-98701412023-01-24 Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain Washington-Hughes, Clorissa L. Roy, Shubhrajit Seneviratne, Herana Kamal Karuppagounder, Senthilkumar S. Morel, Yulemni Jones, Jace W. Zak, Alex Xiao, Tong Boronina, Tatiana N. Cole, Robert N. Bumpus, Namandjé N. Chang, Christopher J. Dawson, Ted M. Lutsenko, Svetlana PLoS Genet Research Article Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl’ cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy. Public Library of Science 2023-01-10 /pmc/articles/PMC9870141/ /pubmed/36626371 http://dx.doi.org/10.1371/journal.pgen.1010558 Text en © 2023 Washington-Hughes et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Washington-Hughes, Clorissa L.
Roy, Shubhrajit
Seneviratne, Herana Kamal
Karuppagounder, Senthilkumar S.
Morel, Yulemni
Jones, Jace W.
Zak, Alex
Xiao, Tong
Boronina, Tatiana N.
Cole, Robert N.
Bumpus, Namandjé N.
Chang, Christopher J.
Dawson, Ted M.
Lutsenko, Svetlana
Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain
title Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain
title_full Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain
title_fullStr Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain
title_full_unstemmed Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain
title_short Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain
title_sort atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870141/
https://www.ncbi.nlm.nih.gov/pubmed/36626371
http://dx.doi.org/10.1371/journal.pgen.1010558
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