Cerebrospinal Fluid from Restless Legs Syndrome Patients Reduces Iron Uptake in Blood-Brain Barrier Endothelial Cells by Disrupting the Regulation of Transferrin Receptors.

OBJECTIVE: Restless legs syndrome (RLS) is a sensorimotor disorder marked by an uncontrollable urge to move the legs. A pathophysiological hallmark of RLS is brain iron deficiency. The endothelial cells (ECs) of the blood-brain barrier (BBB) are responsible for regulating brain iron uptake. Our objective is to determine if brain iron uptake is altered in ECs in RLS. METHODS: Human ECs were generated from induced pluripotent stem cells (iPSCs). ECs were exposed to RLS (n = 14) or control cerebrospinal fluid (CSF) (n = 15), and RESULTS: Free and protein-bound iron in CSF from RLS subjects were decreased compared to controls. Exposure of ECs to RLS CSF significantly decreased the uptake and transport of INTERPRETATION: 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-124-3p. ANN NEUROL 2026.