Prion protein modulates kidney iron metabolism


Brain iron-dyshomeostasis is an important cause of neurotoxicity in prion disorders, a group of neurodegenerative conditions associated with the conversion of prion protein (PrP C ) from its normal conformation to an aggregated, PrP-scrapie (PrP Sc ) isoform. Alteration of iron homeostasis is believed to result from impaired function of PrP C in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrP C is lacking. Kidney provides a relevant model for this evaluation because PrP C is expressed in the kidney, and ~370μg of iron are re-absorbed daily from the glomerular filtrate by kidney proximal tubule cells (PT), requiring ferrireductase activity. Here, we report that PrP C promotes the uptake of transferrin (Tf) and non-Tf-bound-iron (NTBI) by the kidney in vivo, and mainly NTBI by PT cells in vitro. Thus, uptake of 59 Fe administered by gastric gavage, intravenously, or intraperitoneally was significantly lower in PrP-knock-out (PrP -/) mouse kidney relative to PrP +/+ controls. Selective in vivo radiolabeling of plasma NTBI with 59 Fe revealed similar results. Expression of exogenous PrP C in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles, and increased transepithelial transport of 59 Fe-NTBI and to a smaller extent 59 Fe-Tf from the apical to the basolateral domain. Notably, the ferrireductase-deficient mutant of PrP (PrP 5189 ) lacked this activity. Furthermore, excess NTBI and hemin caused aggregation of PrP C to a detergent-insoluble form, limiting iron uptake. Together, these observations suggest that PrP C promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity, and modulates kidney iron

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@inproceedings{Haldar2014PrionPM, title={Prion protein modulates kidney iron metabolism}, author={Swati Haldar and Ajai K. Tripathi and Juan Qian and Amber Beserra and Srinivas Suda and Matthew K Mcelwee and Ulrich Hopfer and Neena Singh}, year={2014} }