Imbalance of iron linked to prion disease-related neuronal demise
WASHINGTON - An Indian-origin researcher at Case Western Reserve University School of Medicine has found that imbalance of iron homeostasis is a common feature of prion disease-affected human, mouse, and hamster brains.
Dr. Neena Singh, who worked in collaboration with researchers from Creighton University, says that her team’s findings provide new insight into the mechanism of neurotoxicity in prion disorders, and novel avenues for the development of therapeutic strategies.
Unlike other neurodegenerative conditions, prion disorders are sporadic, inherited, and infectious, and affect both humans and animals.
Mad cow disease in cattle, scrapie in sheep, and Creutzfeldt-Jakob disease in humans are some of its examples.
The causative agent is a misfolded protein referred to as PrP-scrapie that replicates itself by changing the conformation of neighbouring copies of the same protein, namely the prion protein. Aggregates of PrP-scrapie are toxic to brain cells and cause a spongy-like appearance in diseased brains.
Neena says that her study suggests that accumulation of PrP-scrapie alters the metabolism of iron in diseased brains.
She adds that the imbalance of brain iron homeostasis worsens with disease progression, and is not an outcome of end-stage disease.
Given that iron is highly toxic when mismanaged, the researchers think that this condition may contribute significantly to prion-disease-associated neurotoxicity.
The likely cause of this condition is loss of normal function of the prion protein in cellular iron metabolism, which has recently been shown by Neena and her colleagues, combined with gain of toxic function by the redox-active PrP-scrapie complex.
Neena says that it was surprising to see that prion disease-affected brains are iron deficient, despite a significant increase in their overall iron content.
She concludes that ferritin, a major iron storage protein, co-aggregates with PrP-scrapie in diseased brains and sequesters bound iron in the complex, creating a state of apparent iron deficiency.
The brain cells respond to this condition by increasing their level of iron uptake, and thereby creates a vicious cycle of increased iron uptake in the presence of increased iron.
The resarchers say that their observations may help understand how the prion agent causes neurotoxicity, and enable the development of novel therapeutic strategies targeted at restoring brain iron homeostasis in prion disorders.
A research article on this study has been published in the journal PLoS Pathogens.