Pantothenate kinase-associated neurodegeneration (PKAN) is a
neurodegenerative disease belonging to the group of neurodegeneration with brain
iron accumulation disorders. It is characterized by progressive impairments in movement, speech and cognition. The disease is inherited in a recessive manner due to mutations in the Pantothenate Kinase-2 (PANK2) gene that encodes a
mitochondrial protein involved in
Coenzyme A synthesis. To investigate the link between a PANK2 gene defect and
iron accumulation, we analyzed primary skin fibroblasts from three PKAN patients and three unaffected subjects. The oxidative status of the cells and their ability to respond to
iron were analyzed in both basal and
iron supplementation conditions. In basal conditions, PKAN fibroblasts show an increase in carbonylated
proteins and altered expression of
antioxidant enzymes with respect to the controls. After
iron supplementation, the PKAN fibroblasts had a defective response to the additional
iron. Under these conditions,
ferritins were up-regulated and
Transferrin Receptor 1 (TfR1) was down-regulated to a minor extent in patients compared with the controls. Analysis of
iron regulatory proteins (IRPs) reveals that, with respect to the controls, PKAN fibroblasts have a reduced amount of membrane-associated
mRNA-bound IRP1, which responds imperfectly to
iron. This accounts for the defective expression of
ferritin and TfR1 in patients' cells. The inaccurate quantity of these
proteins produced a higher bioactive labile
iron pool and consequently increased
iron-dependent
reactive oxygen species formation. Our results suggest that Pank2 deficiency promotes an increased oxidative status that is further enhanced by the addition of
iron, potentially causing damage in cells.