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...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010558 |
| _version_ | 1797833062900301824 |
|---|---|
| author | Clorissa L Washington-Hughes Shubhrajit Roy Herana Kamal Seneviratne Senthilkumar S Karuppagounder Yulemni Morel Jace W Jones Alex Zak Tong Xiao Tatiana N Boronina Robert N Cole Namandjé N Bumpus Christopher J Chang Ted M Dawson Svetlana Lutsenko |
| author_facet | Clorissa L Washington-Hughes Shubhrajit Roy Herana Kamal Seneviratne Senthilkumar S Karuppagounder Yulemni Morel Jace W Jones Alex Zak Tong Xiao Tatiana N Boronina Robert N Cole Namandjé N Bumpus Christopher J Chang Ted M Dawson Svetlana Lutsenko |
| author_sort | Clorissa L Washington-Hughes |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-09T14:18:47Z |
| format | Article |
| id | doaj.art-b5e860a5363242f8aa88ed079f2f21e7 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-09T14:18:47Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-b5e860a5363242f8aa88ed079f2f21e72023-05-05T05:30:47ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-01-01191e101055810.1371/journal.pgen.1010558Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain.Clorissa L Washington-HughesShubhrajit RoyHerana Kamal SeneviratneSenthilkumar S KaruppagounderYulemni MorelJace W JonesAlex ZakTong XiaoTatiana N BoroninaRobert N ColeNamandjé N BumpusChristopher J ChangTed M DawsonSvetlana LutsenkoCopper (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.https://doi.org/10.1371/journal.pgen.1010558 |
| spellingShingle | Clorissa L Washington-Hughes Shubhrajit Roy Herana Kamal Seneviratne Senthilkumar S Karuppagounder Yulemni Morel Jace W Jones Alex Zak Tong Xiao Tatiana N Boronina Robert N Cole Namandjé N Bumpus Christopher J Chang Ted M Dawson Svetlana Lutsenko Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain. PLoS Genetics |
| 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 |
| url | https://doi.org/10.1371/journal.pgen.1010558 |
| work_keys_str_mv | AT clorissalwashingtonhughes atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT shubhrajitroy atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT heranakamalseneviratne atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT senthilkumarskaruppagounder atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT yulemnimorel atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT jacewjones atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT alexzak atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT tongxiao atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT tatiananboronina atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT robertncole atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT namandjenbumpus atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT christopherjchang atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT tedmdawson atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain AT svetlanalutsenko atp7bdependentchoroidplexusdysfunctioncausestransientcopperdeficitandmetabolicchangesinthedevelopingmousebrain |