Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

•In the choroid plexus of FXTAS subjects there is: Increase of iron deposits.•Decreased of epithelial transferrin, and decreased ferroportin and ceruloplasmin expression.•Altered intracellular distribution of TfR1.•Altered iron transport at the blood-cerebrospinal fluid barrier in FXTAS.•Iron-chelating drugs may help to inhibit the progression of FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.