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A pathophysiological hallmark of RLS is brain iron deficiency. The endothelial cells (ECs) of the blood\u2013brain barrier (BBB) are responsible for regulating brain iron uptake. Our objective is to determine if brain iron uptake is altered in ECs in RLS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human ECs were generated from induced pluripotent stem cells (iPSCs). ECs were exposed to RLS (n\u2009=\u200914) or control cerebrospinal fluid (CSF) (n\u2009=\u200915), and\n                      <jats:sup>57<\/jats:sup>\n                      Fe\u2010Transferrin transport was determined. Immunoblotting and quantitative polymerase chain reaction were used to analyze protein, microRNA (miRNA), and messenger RNA (mRNA) expressions. We performed miRNA and transferrin receptor 1 (TfR1) 3\u2032 iron\u2010responsive elements (IRE) interaction in HEK\u2010293 cells by using a pMIR\u2010REPORTER luciferase vector.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Free and protein\u2010bound iron in CSF from RLS subjects were decreased compared to controls. Exposure of ECs to RLS CSF significantly decreased the uptake and transport of\n                      <jats:sup>57<\/jats:sup>\n                      Fe compared to the control. TfR1 expression decreased while iron regulatory proteins (IRP) increased in RLS\u2010CSF exposed ECs. TfR1 expression was also regulated by miRNAs. The miR\u2010124\u20103p levels were higher in RLS CSF\u2010derived extracellular vesicles than in the control. It binds the TfR1 3\u2032 IRE sequence in the pMIR\u2010REPORTER vector, reducing luciferase expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>When ECs are treated with CSF from RLS patients, they show a profile of iron deficiency, except that the TfR1 expression does not increase as would be predicted. The decrease in TfR1 protein expression is because of a reduction in TfR1 mRNA stability by the binding of increased miR\u2010124\u20103p. ANN NEUROL 2026;100:48\u201358<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78221","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:19:56Z","timestamp":1775625596000},"page":"48-58","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cerebrospinal Fluid from Restless Legs Syndrome Patients Reduces Iron Uptake in Blood\u2013Brain Barrier Endothelial Cells by Disrupting the Regulation of Transferrin Receptors"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2584-5750","authenticated-orcid":false,"given":"Kondaiah","family":"Palsa","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Penn State College of Medicine  Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurosman Pappus","family":"Sahu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Penn State College of Medicine  Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Rye","sequence":"additional","affiliation":[{"name":"Department of Neurology and Emory Sleep Center Emory University School of Medicine  Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2329-6847","authenticated-orcid":false,"given":"Lynn Marie","family":"Trotti","sequence":"additional","affiliation":[{"name":"Department of Neurology and Emory Sleep Center Emory University School of Medicine  Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina A.","family":"Elcheva","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics Penn State College of Medicine  Hershey PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir 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