Is ferroportin–hepcidin signaling altered in restless legs syndrome?☆

Abstract 

Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs. Sufferers of RLS often experience chronic sleep deprivation, due to the characteristic worsening of symptoms both when at rest and during the night. MRI data, autopsy studies, and a consistent decrease in CSF ferritin all suggest that early-onset RLS is associated with insufficient iron in the brain. In this study, we examined the relationship between the iron regulatory hormone hepcidin and RLS. Hepcidin serves as a hormone that signals iron release from cells by interacting with ferroportin. We measured the expression and concentration of pro-hepcidin in the brain and cerebrospinal fluid of both RLS patients and control individuals. In CSF, we found that pro-hepcidin levels were significantly decreased in early-onset RLS patient samples, but not in late-onset RLS patients, when compared to controls. Conversely, in neuromelanin cells, substantia nigra, and putamen, the concentration of pro-hepcidin in RLS samples is significantly increased compared to controls. Functionally, hepcidin binds to ferroportin to limit iron movement from cells. Therefore, we provide immunocytochemical evidence that ferroportin is expressed by the epithelial cells of the choroid plexus and the ependymal cells lining the ventricles. These data suggest that sites of action for hepcidin include signaling the ventricular system for movement between brain and CSF. At this time, it cannot be determined if the lower levels of pro-hepcidin in the CSF represent a compensatory response to the decreased levels of iron in the brain or a defective signaling mechanism in RLS. Nonetheless, these data support the mounting evidence that there is a biological basis for RLS and the underlying mechanism involves iron management.

Keywords: Basal ganglia disorders, Movement disorders, Iron, Cerebrospinal fluid (CSF), Laser capture microdissection (LCM), Neuromelanin, Putamen