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Prion protein modulates cellular iron uptake: a novel function with implications for prion disease pathogenesis
Ajay Singh1, Maradumane L Mohan, Alfred Orina Isaac
1The Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Plos One
|February 13, 2009
Summary
Prion protein (PrP(C)) facilitates cellular iron uptake and transport. Mutations in PrP can disrupt iron homeostasis, contributing to neurotoxicity in prion diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Prion diseases involve the misfolding of prion protein (PrP(C)) into a neurotoxic form (PrP(Sc)).
- Iron homeostasis imbalance is observed in prion-infected cells and models, suggesting a role for redox-iron in pathogenesis.
- The normal function of PrP(C) and the precise mechanism of PrP(Sc) toxicity remain unclear.
Purpose of the Study:
- To investigate the role of PrP(C) in cellular iron uptake and transport.
- To examine how mutant PrP forms affect cellular iron levels and homeostasis.
- To elucidate the contribution of PrP(C) dysfunction to iron imbalance in prion disorders.
Main Methods:
- Utilized human neuroblastoma cells overexpressing wild-type PrP(C) and various mutant PrP forms.
- Quantified total cellular iron, labile iron pool (LIP), and ferritin iron content.
- Assessed the expression levels of iron uptake proteins (transferrin, transferrin receptor) and iron storage protein (ferritin).
- Manipulated PrP(C) localization via endocytosis stimulation and plasma membrane cross-linking.
Main Results:
- Overexpression of PrP(C) increased intracellular iron, LIP, and ferritin iron, while decreasing transferrin and transferrin receptor levels.
- Stimulating PrP(C) endocytosis enhanced its effect on ferritin iron, whereas plasma membrane cross-linking reversed it.
- Mutant PrP forms, particularly those lacking octapeptide-repeats or the membrane anchor, or carrying the PrP(102L) mutation, decreased ferritin iron content.
- The impact of mutations on LIP and transferrin/receptor levels was complex and mutation-dependent.
- PrP forms did not affect iron release into the medium, indicating a role in cellular uptake and transport.
Conclusions:
- PrP(C) plays a crucial role in mediating cellular iron uptake and transport to ferritin.
- Dysfunctional PrP(C), particularly due to mutations, contributes significantly to brain iron imbalance in prion diseases.
- Understanding PrP(C)-iron interactions may offer new therapeutic targets for prion disorders.
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