Prion Protein Modulates Cellular Iron Uptake: A Novel Function with Implications for Prion Disease Pathogenesis Export

@article{citeulike:4041902, abstract = {<p>Converging evidence leaves little doubt that a change in the conformation of prion protein (PrP^C) from a mainly α-helical to a β-sheet rich PrP-scrapie (PrP^Sc) form is the main event responsible for prion disease associated neurotoxicity. However, neither the mechanism of toxicity by PrP^Sc, nor the normal function of PrP^C is entirely clear. Recent reports suggest that imbalance of iron homeostasis is a common feature of prion infected cells and mouse models, implicating redox-iron in prion disease pathogenesis. In this report, we provide evidence that PrP^C mediates cellular iron uptake and transport, and mutant PrP forms alter cellular iron levels differentially. Using human neuroblastoma cells as models, we demonstrate that over-expression of PrP^C increases intra-cellular iron relative to non-transfected controls as indicated by an increase in total cellular iron, the cellular labile iron pool (LIP), and iron content of ferritin. As a result, the levels of iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) are decreased, and expression of iron storage protein ferritin is increased. The positive effect of PrP^C on ferritin iron content is enhanced by stimulating PrP^C endocytosis, and reversed by cross-linking PrP^C on the plasma membrane. Expression of mutant PrP forms lacking the octapeptide-repeats, the membrane anchor, or carrying the pathogenic mutation PrP^102L decreases ferritin iron content significantly relative to PrP^C expressing cells, but the effect on cellular LIP and levels of Tf, TfR, and ferritin is complex, varying with the mutation. Neither PrP^C nor the mutant PrP forms influence the rate or amount of iron released into the medium, suggesting a functional role for PrP^C in cellular iron uptake and transport to ferritin, and dysfunction of PrP^C as a significant contributing factor of brain iron imbalance in prion disorders.</p>}, author = {Singh, Ajay and Mohan, Maradumane L. and Isaac, Alfred O. and Luo, Xiu and Petrak, Jiri and Vyoral, Daniel and Singh, Neena}, citeulike-article-id = {4041902}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pone.0004468}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19212444}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19212444}, day = {12}, doi = {10.1371/journal.pone.0004468}, journal = {PLoS ONE}, keywords = {function, iron, pathogenesis, prion, protein, transport}, month = {February}, number = {2}, pages = {e4468+}, posted-at = {2009-02-13 01:45:34}, priority = {2}, publisher = {Public Library of Science}, title = {Prion Protein Modulates Cellular Iron Uptake: A Novel Function with Implications for Prion Disease Pathogenesis}, url = {http://dx.doi.org/10.1371/journal.pone.0004468}, volume = {4}, year = {2009} }

TY - JOUR ID - citeulike:4041902 L3 - citeulike-article-id:4041902 N2 - <p>Converging evidence leaves little doubt that a change in the conformation of prion protein (PrP^C) from a mainly α-helical to a β-sheet rich PrP-scrapie (PrP^Sc) form is the main event responsible for prion disease associated neurotoxicity. However, neither the mechanism of toxicity by PrP^Sc, nor the normal function of PrP^C is entirely clear. Recent reports suggest that imbalance of iron homeostasis is a common feature of prion infected cells and mouse models, implicating redox-iron in prion disease pathogenesis. In this report, we provide evidence that PrP^C mediates cellular iron uptake and transport, and mutant PrP forms alter cellular iron levels differentially. Using human neuroblastoma cells as models, we demonstrate that over-expression of PrP^C increases intra-cellular iron relative to non-transfected controls as indicated by an increase in total cellular iron, the cellular labile iron pool (LIP), and iron content of ferritin. As a result, the levels of iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) are decreased, and expression of iron storage protein ferritin is increased. The positive effect of PrP^C on ferritin iron content is enhanced by stimulating PrP^C endocytosis, and reversed by cross-linking PrP^C on the plasma membrane. Expression of mutant PrP forms lacking the octapeptide-repeats, the membrane anchor, or carrying the pathogenic mutation PrP^102L decreases ferritin iron content significantly relative to PrP^C expressing cells, but the effect on cellular LIP and levels of Tf, TfR, and ferritin is complex, varying with the mutation. Neither PrP^C nor the mutant PrP forms influence the rate or amount of iron released into the medium, suggesting a functional role for PrP^C in cellular iron uptake and transport to ferritin, and dysfunction of PrP^C as a significant contributing factor of brain iron imbalance in prion disorders.</p> IS - 2 JF - PLoS ONE TI - Prion Protein Modulates Cellular Iron Uptake: A Novel Function with Implications for Prion Disease Pathogenesis PB - Public Library of Science VL - 4 SP - e4468 KW - function KW - iron KW - pathogenesis KW - prion KW - protein KW - transport AU - Singh, Ajay AU - Mohan, Maradumane AU - Isaac, Alfred AU - Luo, Xiu AU - Petrak, Jiri AU - Vyoral, Daniel AU - Singh, Neena PY - 2009/02/12/ UR - http://dx.doi.org/10.1371/journal.pone.0004468 ER -