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Prion protein modulates cellular iron uptake: a novel function with implications for prion disease pathogenesis.
- Source :
-
PloS one [PLoS One] 2009; Vol. 4 (2), pp. e4468. Date of Electronic Publication: 2009 Feb 12. - Publication Year :
- 2009
-
Abstract
- Converging evidence leaves little doubt that a change in the conformation of prion protein (PrP(C)) from a mainly alpha-helical to a beta-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.
- Subjects :
- Animals
Biological Transport physiology
Cell Line, Tumor
Endocytosis physiology
Ferritins metabolism
Humans
Mice
Neuroblastoma metabolism
Prion Diseases genetics
Prions chemistry
Prions genetics
Protein Isoforms chemistry
Protein Isoforms genetics
Protein Isoforms metabolism
Receptors, Transferrin genetics
Receptors, Transferrin metabolism
Transferrin genetics
Transferrin metabolism
Iron metabolism
Prion Diseases etiology
Prion Diseases metabolism
Prions metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 4
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 19212444
- Full Text :
- https://doi.org/10.1371/journal.pone.0004468