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

doi:10.1371/journal.pgen.1010558

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

Journal Article · Tue Jan 10 00:00:00 EST 2023 · PLoS Genetics

DOI:https://doi.org/10.1371/journal.pgen.1010558· OSTI ID:1975399

Washington-Hughes, Clorissa L. ^[1]; Roy, Shubhrajit ^[1];

^[2]; Karuppagounder, Senthilkumar S. ^[3];

^[4]; Jones, Jace W. ^[4]; Zak, Alex ^[1];

^[5]; Boronina, Tatiana N. ^[2];

^[2]; Bumpus, Namandjé N. ^[2]; Chang, Christopher J. ^[4]; Dawson, Ted M. ^[3];

^[1]

Johns Hopkins University, Baltimore, MD (United States)
Johns Hopkins University, Baltimore, MD (United States). School of Medicine
Johns Hopkins University, Baltimore, MD (United States). School of Medicine; Johns Hopkins University, Baltimore, MD (United States)
University of Maryland, College Park, MD (United States)
University of California, Berkeley, CA (United States)

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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Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences & Biosciences Division (CSGB); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231; P30 DK089502; UL1 TR003098; R01 GM101502; R01 GM103853; R01 AG064908; GM 79465

OSTI ID:: 1975399

Journal Information:: PLoS Genetics, Vol. 19, Issue 1; ISSN 1553-7404

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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cell membranes
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epithelial cells
membrane staining
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cerebrospinal fluid
cytoskeleton
immunofluorescence staining

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

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