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

Abstract

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.

Authors:

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)

Publication Date:: Tue Jan 10 00:00:00 EST 2023

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

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

OSTI Identifier:: 1975399

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

Resource Type:: Accepted Manuscript

Journal Name:: PLoS Genetics

Additional Journal Information:: Journal Volume: 19; Journal Issue: 1; Journal ID: ISSN 1553-7404

Publisher:: Public Library of Science

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; cell membranes; choroid plexus; epithelial cells; membrane staining; Wilson's disease; cerebrospinal fluid; cytoskeleton; immunofluorescence staining

Citation Formats


                    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., and Lutsenko, Svetlana. Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain.  United States: N. p., 2023. 
Web.  doi:10.1371/journal.pgen.1010558.

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                    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.  United States.  https://doi.org/10.1371/journal.pgen.1010558

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                    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., and Lutsenko, Svetlana. Tue .  
"Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain".  United States.  https://doi.org/10.1371/journal.pgen.1010558.  https://www.osti.gov/servlets/purl/1975399.

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@article{osti_1975399,

  title        = {Atp7b-dependent choroid plexus dysfunction causes transient copper deficit and metabolic changes in the developing mouse brain},

  author       = {Washington-Hughes, Clorissa L. and Roy, Shubhrajit and Seneviratne, Herana Kamal and Karuppagounder, Senthilkumar S. and Morel, Yulemni and Jones, Jace W. and Zak, Alex and Xiao, Tong and Boronina, Tatiana N. and Cole, Robert N. and Bumpus, Namandjé N. and Chang, Christopher J. and Dawson, Ted M. and Lutsenko, Svetlana},

  abstractNote = {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.},

  doi          = {10.1371/journal.pgen.1010558},

  journal      = {PLoS Genetics},

  number       = 1,

  volume       = 19,

  place        = {United States},

  year         = {Tue Jan 10 00:00:00 EST 2023},

  month        = {Tue Jan 10 00:00:00 EST 2023}

}

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

Abstract

Citation Formats

ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase journal, October 2018

Urinary Copper Elevation in a Mouse Model of Wilson's Disease Is a Regulated Process to Specifically Decrease the Hepatic Copper Load journal, June 2012

Wilson disease journal, September 2018

Neuropsychological findings in treated Wilson's disease* journal, January 2009

Psychiatric manifestations in Wilson’s disease: possibilities and difficulties for treatment journal, March 2018

Locations and contributions of the phosphotransferases EPT1 and CEPT1 to the biosynthesis of ethanolamine phospholipids journal, August 2020

Neurological and neuropsychiatric spectrum of Wilson's disease: a prospective study of 45 cases journal, August 1991

Dopamine Beta-Hydroxylase of Adrenal Chromaffin Granules: Structure and Function journal, June 1988

Neurologic impairment in Wilson disease journal, April 2019

Myosin motor function: the ins and outs of actin-based membrane protrusions journal, January 2010

The Function of ATPase Copper Transporter ATP7B in Intestine journal, January 2018

Serum Neurofilament Light Chain as a Biomarker of Brain Injury in Wilson's Disease: Clinical and Neuroradiological Correlations journal, February 2022

Null Mutation of the Murine ATP7B (Wilson Disease) Gene Results in Intracellular Copper Accumulation and Late-Onset Hepatic Nodular Transformation journal, September 1999

Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species journal, July 2013

Pyrylium Salts as Reactive Matrices for MALDI-MS Imaging of Biologically Active Primary Amines journal, March 2015

Wilson disease and psychiatric symptoms: A brief case report journal, July 2019

Development of the catecholamine neurons in human embryos and fetuses, with special emphasis on the innervaton of the cerebral cortex journal, January 1995

Wilson Disease: Update on Pathophysiology and Treatment journal, May 2022

Relative contribution of CTR1 and DMT1 in copper transport by the blood–CSF barrier: Implication in manganese-induced neurotoxicity journal, May 2012

Lipid extraction by methyl- tert -butyl ether for high-throughput lipidomics journal, February 2008

Peptidylglycine alpha-amidating monooxygenase (PAM) in Schwann cells and glia as well as neurons. journal, September 1990

Wilson disease: not just a copper disorder. Analysis of a Wilson disease model demonstrates the link between copper and lipid metabolism journal, January 2007

Apoptosis in cerebrum of macular mutant mouse journal, April 2002

Consequences of Copper Accumulation in the Livers of the Atp7b−/− (Wilson Disease Gene) Knockout Mice journal, February 2006

Neurological manifestations in Wilson's disease: Report of 119 cases journal, January 2006

Neonatal Diagnosis and Treatment of Menkes Disease journal, February 2008

Effects of copper metabolism on neurological functions in Wistar and Wilson’s disease model rats journal, October 2006

The c-Abl inhibitor, Nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease journal, May 2014

Clinical Assessment of 31 Patients With Wilson's Disease journal, April 1987

Wilson Disease at a Single Cell Level: INTRACELLULAR COPPER TRAFFICKING ACTIVATES COMPARTMENT-SPECIFIC RESPONSES IN HEPATOCYTES journal, July 2010

Lipid and energy metabolism in Wilson disease journal, March 2020

MR Imaging of the Brain in Neurologic Wilson Disease journal, January 2019

Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease journal, November 2013

Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation journal, December 2017

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading journal, October 2006

Regulation of Copper Transport Crossing Brain Barrier Systems by Cu-ATPases: Effect of Manganese Exposure journal, March 2014

The Copper-transporting ATPases, Menkes and Wilson Disease Proteins, Have Distinct Roles in Adult and Developing Cerebellum journal, March 2005

Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system journal, June 2018

Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis journal, September 2019

Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model journal, September 2018

Cilia-based peptidergic signaling journal, December 2019

A bioactive peptide amidating enzyme is required for ciliogenesis journal, May 2017

Genetic and pharmacological inactivation of apical Na+-K+-2Cl−cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter journal, April 2019

Copper regulates cyclic-AMP-dependent lipolysis journal, June 2016

MALDI Mass Spectrometry Imaging Reveals Heterogeneous Distribution of Tenofovir and Tenofovir Diphosphate in Colorectal Tissue of Subjects Receiving a Tenofovir-Containing Enema journal, July 2018

ATP7B knockout disturbs copper and lipid metabolism in Caco-2 cells journal, March 2020

Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain journal, August 2010

Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson’s disease journal, January 2021

Evaluation of the accuracy of exchangeable copper and relative exchangeable copper (REC) in a mouse model of Wilson’s disease journal, December 2018

Age-dependent changes of cerebral copper metabolism in Atp7b −/− knockout mouse model of Wilson’s disease by [64Cu]CuCl2-PET/CT journal, January 2017

Mechanism of copper transport at the blood–cerebrospinal fluid barrier: influence of iron deficiency in an in vitro model journal, March 2012

Brain copper storage after genetic long-term correction in a mouse model of Wilson disease journal, May 2018

Searching for harmony in transition-metal signaling journal, September 2015

Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease journal, March 2021

Psychiatric aspects of Wilson disease: a review journal, January 2014

Advanced catecholaminergic disturbances in the brain in a case of Wilson's disease journal, January 1982

Advances in visualization of copper in mammalian systems using X-ray fluorescence microscopy journal, April 2020

ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase
journal, October 2018

Urinary Copper Elevation in a Mouse Model of Wilson's Disease Is a Regulated Process to Specifically Decrease the Hepatic Copper Load
journal, June 2012

Wilson disease
journal, September 2018

Neuropsychological findings in treated Wilson's disease*
journal, January 2009

Psychiatric manifestations in Wilson’s disease: possibilities and difficulties for treatment
journal, March 2018

Locations and contributions of the phosphotransferases EPT1 and CEPT1 to the biosynthesis of ethanolamine phospholipids
journal, August 2020

Neurological and neuropsychiatric spectrum of Wilson's disease: a prospective study of 45 cases
journal, August 1991

Dopamine Beta-Hydroxylase of Adrenal Chromaffin Granules: Structure and Function
journal, June 1988

Neurologic impairment in Wilson disease
journal, April 2019

Myosin motor function: the ins and outs of actin-based membrane protrusions
journal, January 2010

The Function of ATPase Copper Transporter ATP7B in Intestine
journal, January 2018

Serum Neurofilament Light Chain as a Biomarker of Brain Injury in Wilson's Disease: Clinical and Neuroradiological Correlations
journal, February 2022

Null Mutation of the Murine ATP7B (Wilson Disease) Gene Results in Intracellular Copper Accumulation and Late-Onset Hepatic Nodular Transformation
journal, September 1999

Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species
journal, July 2013

Pyrylium Salts as Reactive Matrices for MALDI-MS Imaging of Biologically Active Primary Amines
journal, March 2015

Wilson disease and psychiatric symptoms: A brief case report
journal, July 2019

Development of the catecholamine neurons in human embryos and fetuses, with special emphasis on the innervaton of the cerebral cortex
journal, January 1995

Wilson Disease: Update on Pathophysiology and Treatment
journal, May 2022

Relative contribution of CTR1 and DMT1 in copper transport by the blood–CSF barrier: Implication in manganese-induced neurotoxicity
journal, May 2012

Lipid extraction by methyl- tert -butyl ether for high-throughput lipidomics
journal, February 2008

Peptidylglycine alpha-amidating monooxygenase (PAM) in Schwann cells and glia as well as neurons.
journal, September 1990

Wilson disease: not just a copper disorder. Analysis of a Wilson disease model demonstrates the link between copper and lipid metabolism
journal, January 2007

Apoptosis in cerebrum of macular mutant mouse
journal, April 2002

Consequences of Copper Accumulation in the Livers of the Atp7b−/− (Wilson Disease Gene) Knockout Mice
journal, February 2006

Neurological manifestations in Wilson's disease: Report of 119 cases
journal, January 2006

Neonatal Diagnosis and Treatment of Menkes Disease
journal, February 2008

Effects of copper metabolism on neurological functions in Wistar and Wilson’s disease model rats
journal, October 2006

The c-Abl inhibitor, Nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease
journal, May 2014

Clinical Assessment of 31 Patients With Wilson's Disease
journal, April 1987

Wilson Disease at a Single Cell Level: INTRACELLULAR COPPER TRAFFICKING ACTIVATES COMPARTMENT-SPECIFIC RESPONSES IN HEPATOCYTES
journal, July 2010

Lipid and energy metabolism in Wilson disease
journal, March 2020

MR Imaging of the Brain in Neurologic Wilson Disease
journal, January 2019

Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease
journal, November 2013

Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation
journal, December 2017

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading
journal, October 2006

Regulation of Copper Transport Crossing Brain Barrier Systems by Cu-ATPases: Effect of Manganese Exposure
journal, March 2014

The Copper-transporting ATPases, Menkes and Wilson Disease Proteins, Have Distinct Roles in Adult and Developing Cerebellum
journal, March 2005

Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system
journal, June 2018

Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis
journal, September 2019

Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model
journal, September 2018

Cilia-based peptidergic signaling
journal, December 2019

A bioactive peptide amidating enzyme is required for ciliogenesis
journal, May 2017

Genetic and pharmacological inactivation of apical Na⁺-K⁺-2Cl⁻cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter
journal, April 2019

Copper regulates cyclic-AMP-dependent lipolysis
journal, June 2016

MALDI Mass Spectrometry Imaging Reveals Heterogeneous Distribution of Tenofovir and Tenofovir Diphosphate in Colorectal Tissue of Subjects Receiving a Tenofovir-Containing Enema
journal, July 2018

ATP7B knockout disturbs copper and lipid metabolism in Caco-2 cells
journal, March 2020

Somatic mosaicism in Menkes disease suggests choroid plexus-mediated copper transport to the developing brain
journal, August 2010

Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson’s disease
journal, January 2021

Evaluation of the accuracy of exchangeable copper and relative exchangeable copper (REC) in a mouse model of Wilson’s disease
journal, December 2018

Age-dependent changes of cerebral copper metabolism in Atp7b −/− knockout mouse model of Wilson’s disease by [64Cu]CuCl2-PET/CT
journal, January 2017

Mechanism of copper transport at the blood–cerebrospinal fluid barrier: influence of iron deficiency in an in vitro model
journal, March 2012

Brain copper storage after genetic long-term correction in a mouse model of Wilson disease
journal, May 2018

Searching for harmony in transition-metal signaling
journal, September 2015

Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease
journal, March 2021

Psychiatric aspects of Wilson disease: a review
journal, January 2014

Advanced catecholaminergic disturbances in the brain in a case of Wilson's disease
journal, January 1982

Advances in visualization of copper in mammalian systems using X-ray fluorescence microscopy
journal, April 2020