Prion Disease Pathogenesis - Recent Advances in Microbiology - page 56

Chapter 5
Prion Disease Pathogenesis
Ajay Singh, Maradumane L. Mohan, Alfred Orina Isaac, Xiu Luo,
Jiri Petrak, Daniel Vyoral, and Neena Singh
INTRODUCTION
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 patho-
genesis. 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
intracellular 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 endo-
cytosis, 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 influ-
ence 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.
The PrP C is an evolutionarily conserved cell surface glycoprotein expressed abun-
dantly on neuronal cells. Despite its ubiquitous presence, the physiological function
of PrP C has remained ambiguous. The best characterized role for this protein remains
its involvement in the pathogenesis of familial, infectious, and sporadic prion disor-
ders, where a change in the conformation of PrP C from a mainly α-helical to a β-sheet
rich PrP Sc form renders it infectious and pathogenic [1-5]. The mechanism by which
PrP Sc induces neurotoxicity, however, is not clear. Studies over the past decade have
clarifi ed several aspects of this process [1, 6, 7]. Prominent among these is the resis-
tance of transgenic mice lacking neuronal PrPC expression to PrP Sc induced toxicity,
implicating PrP C as the principal mediator of the neurotoxic signal [8, 9]. However,
prion infected transgenic mice expressing PrP C only on astrocytes accumulate PrP Sc
and succumb to disease [10], leaving the matter unresolved. Adding to the complexity