{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T02:32:33Z","timestamp":1781663553015,"version":"3.54.5"},"reference-count":0,"publisher":"American Society for Cell Biology (ASCB)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"abstract":"<jats:p>\n                    Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that produced a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 KO cells revealed simultaneous upregulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis. Spatial transcriptomic profiling of Atp7a\n                    <jats:sup>flx\/<\/jats:sup>\n                    <jats:sup>Y<\/jats:sup>\n                    :: Vil1\n                    <jats:sup>Cre\/+<\/jats:sup>\n                    mice identified upregulated protein synthesis machinery and mTORC1-S6K pathway genes in copper-deficient Purkinje neurons in the cerebellum. Genetic epistasis experiments in Drosophila demonstrated that copper deficiency dendritic phenotypes in class IV neurons are improved or rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper deficiency.\n                  <\/jats:p>","DOI":"10.1091\/mbc.e24-11-0512","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T10:21:30Z","timestamp":1738146090000},"source":"Crossref","is-referenced-by-count":4,"title":["Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration"],"prefix":"10.1091","author":[{"given":"Alicia R.","family":"Lane","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Emory University, 615 Michael St, Atlanta, GA, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah E.","family":"Scher","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, 615 Michael St, Atlanta, GA, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shatabdi","family":"Bhattacharjee","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Zlatic","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, 615 Michael St, Atlanta, GA, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University, 1510 Clifton Rd, Atlanta, Georgia, USA, 30322"},{"name":"Department of Neurology, Emory University, 12 Executive Park Dr NE, Atlanta, Georgia, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avanti","family":"Gokhale","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, 615 Michael St, Atlanta, GA, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaela S.","family":"Singleton","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, 615 Michael St, Atlanta, GA, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duc M.","family":"Duong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University, 1510 Clifton Rd, Atlanta, Georgia, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"McKenna","sequence":"additional","affiliation":[{"name":"NanoString Technologies, 530 Fairview Ave N, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William L.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton Rd, Atlanta, Georgia, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Baiju","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton Rd, Atlanta, Georgia, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix G Rivera","family":"Moctezuma","sequence":"additional","affiliation":[{"name":"George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA 30332"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommy","family":"Tran","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atit A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren B.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Biophysics and Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University, Corvallis, OR 97331"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Petris","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry, Molecular Microbiology and Immunology, Ophthalmology, and Christopher S. Bond Life Sciences Center, 1201 Rollins Street, University of Missouri, Columbia, MO, 65211"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levi B.","family":"Wood","sequence":"additional","affiliation":[{"name":"George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA 30332"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupam","family":"Patgiri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Emory University, 1510 Clifton Rd, Atlanta, Georgia, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alysia D.","family":"Vrailas-Mortimer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Biophysics and Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University, Corvallis, OR 97331"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N.","family":"Cox","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blaine R.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University, 1510 Clifton Rd, Atlanta, Georgia, USA, 30322"},{"name":"Department of Neurology, Emory University, 12 Executive Park Dr NE, Atlanta, Georgia, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, 615 Michael St, Atlanta, GA, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Faundez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, 615 Michael St, Atlanta, GA, USA, 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1076","published-online":{"date-parts":[[2025,1,29]]},"container-title":["Molecular Biology of the Cell"],"original-title":[],"language":"en","deposited":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T10:07:27Z","timestamp":1738663647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.molbiolcell.org\/doi\/10.1091\/mbc.E24-11-0512"}},"subtitle":[],"editor":[{"given":"Avital Adah","family":"Rodal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":0,"alternative-id":["10.1091\/mbc.E24-11-0512"],"URL":"https:\/\/doi.org\/10.1091\/mbc.e24-11-0512","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.09.09.612106","asserted-by":"object"}]},"ISSN":["1059-1524","1939-4586"],"issn-type":[{"value":"1059-1524","type":"print"},{"value":"1939-4586","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,29]]},"article-number":"mbc.E24-11-0512"}}