Abnormal Brain Iron Homeostasis in Human and Animal Prion Disorders

Abstract

Neurotoxicity in all prion disorders is believed to result from the accumulation of PrP-scrapie (PrPSc), a β-sheet rich isoform of a normal cell-surface glycoprotein, the prion protein (PrPC). Limited reports suggest imbalance of brain iron homeostasis as a significant associated cause of neurotoxicity in prion-infected cell and mouse models. However, systematic studies on the generality of this phenomenon and the underlying mechanism(s) leading to iron dyshomeostasis in diseased brains are lacking. In this report, we demonstrate that prion disease–affected human, hamster, and mouse brains show increased total and redox-active Fe (II) iron, and a paradoxical increase in major iron uptake proteins transferrin (Tf) and transferrin receptor (TfR) at the end stage of disease. Furthermore, examination of scrapie-inoculated hamster brains at different timepoints following infection shows increased levels of Tf with time, suggesting increasing iron deficiency with disease progression. Sporadic Creutzfeldt-Jakob disease (sCJD)–affected human brains show a similar increase in total iron and a direct correlation between PrP and Tf levels, implicating PrPSc as the underlying cause of iron deficiency. Increased binding of Tf to the cerebellar Purkinje cell neurons of sCJD brains further indicates upregulation of TfR and a phenotype of neuronal iron deficiency in diseased brains despite increased iron levels. The likely cause of this phenotype is sequestration of iron in brain ferritin that becomes detergent-insoluble in PrPSc-infected cell lines and sCJD brain homogenates. These results suggest that sequestration of iron in PrPSc–ferritin complexes induces a state of iron bio-insufficiency in prion disease–affected brains, resulting in increased uptake and a state of iron dyshomeostasis. An additional unexpected observation is the resistance of Tf to digestion by proteinase-K, providing a reliable marker for iron levels in postmortem human brains. These data implicate redox-iron in prion disease–associated neurotoxicity, a novel observation with significant implications for prion disease pathogenesis.

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…The noxious activity of PrPsc is not defined yet. Interestingly mice lacking the gene showed signs of systemic iron deficiency (Singh et al 2009b) and a progressive decrease of the metal is described in brains from affected patients or animals, despite an increase in total iron load (Singh et al 2009a) together with loss of function of PrPC. There is evidence that PrPc could have ferroxidase activity and its absence could reduce iron uptake in diseased brain (Singh et al 2013), but an important role could be attributed to the formation of aggregates between the PrPsc and iron-rich ferritin (Singh et al 2012).…”

Metals in obex and retropharyngeal lymph nodes of Illinois white-tailed deer and their variations associated with CWD status

“…16 PrP Sc , on the other hand, is the pathogenic agent in all TSEs, as changes in conformation of PrP C to PrP Sc induce pathological modifications such as: neurotoxicity due to disruption of PrP C normal function and imbalance in metal homeostasis in the brain, physical damage of membranes by PrP Sc aggregation, and apoptosis as a result of intracellular PrP Sc accumulation. 10,[17][18][19] Moreover, TSE neurotoxicity, associated with imbalance in brain homeostasis and deregulation of metals, has been previously observed for other neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). 9 PrP C -metal interactions differ with each metal and may play a physiological or pathological role.…”

“…17 Additionally, increased total and redox-active Fe (II), together with increased levels of transport and storage proteins, such as transferrin (Tf) and transferrin receptors (TfR), play a crucial role in Fe dyshomestasis and associated neurotoxicity in prion infected human, mouse and hamster brains. 10 Interestingly, reduced levels of Fe in presence of excess total Fe was found to be a characteristic associated with prion diseases, but not with other neurodegenerative diseases such as AD and PD. 10 A combined decrease in Cu with an increase in Mn in blood and brain has been detected prior to disease onset in BSE infected cattle and Scrapie-infected mice and sheep, as well as in brain synaptosomes of Scrapie-infected mice.…”

“…The exact physiological roles of PrP C are still under investigation, but many studies have suggested its participation in the metabolism of metals and its role as antioxidant (superoxide dismutase (SOD)-like activity). [6][7][8][9][10] Although the potential redox activity of PrP C has been previously demonstrated, this is controversial since other studies dispute the SOD function of PrP C . 11,12 The interaction of PrP C with metals such as iron (Fe), copper (Cu) and manganese (Mn) is important, since these metals serve as cofactors for enzymes, and play important roles in mammalian biochemical processes.…”

“…9,18 TSEs like Scrapie and Sporadic CreutzfeldtJacob disease have been linked to changes in Fe metabolism that contribute to accumulation of PrP Sc , sequestration of Fe in PrP Sc -ferritin complexes, and neurotoxicity associated to upregulation of Fe intake into the brain. 10,17 Furthermore, Fe binding to PrP C contributes to conformational changes that provide PrP Sc stability and resistance to proteinase K (PK) digestion. The formation of PrP Sc -ferritin complexes resulting from the upregulation of PrP C and ferritin within the lysosome, ultimately contributes to PrP Sc generation and propagation, even in absence of the infectious PrP Sc .…”