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MBC in Press, published online ahead of print June 13, 2007
Mol. Biol. Cell 10.1091/mbc.E07-04-0317

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Submitted on April 9, 2007
Revised on May 31, 2007
Accepted on June 4, 2007

Modulation of PK-resistant PrP in Cells and Infectious Brain Homogenate by Redox-Iron: Implications for Prion Replication and Disease Pathogenesis

Subhabrata Basu,*{dagger}; Maradumane L. Mohan,*{dagger} Xiu Luo,*{dagger} Bishwajit Kundu,{ddagger} Qingzhong Kong,* and Neena Singh*

*Department of Pathology, Case Western Reserve University, Cleveland, OH 44106; {ddagger}Department of Biochemical Engineering and Biotechnology, The Indian Institute of Technology, New Delhi, India

Monitoring Editor: Jonathan Weissman

The principal infectious and pathogenic agent in all prion disorders is a {beta}-sheet rich isoform of the cellular prion protein (PrPC) termed PrP-scrapie (PrPSc). Once initiated, PrPSc is self replicating and toxic to neuronal cells, but the underlying mechanisms remain unclear. In this report we demonstrate that PrPC binds iron and transforms to a PrPSc-like form (*PrPSc) when human neuroblastoma cells are exposed to an inorganic source of redox-iron. The *PrPSc thus generated is itself redox-active and induces the transformation of additional PrPC, simulating *PrPSc propagation in the absence of brain derived PrPSc. Moreover, limited depletion of iron from prion disease affected human and mouse brain homogenates and scrapie infected mouse neuroblastoma cells results in 4-10-fold reduction in proteinase-K (PK) resistant PrPSc, implicating redox iron in the generation, propagation, and stability of PK-resistant PrPSc. Furthermore, we demonstrate increased redox-active ferrous iron levels in prion disease affected brains, suggesting that accumulation of PrPSc is modulated by the combined effect of imbalance in brain iron homeostasis and redox-active nature of PrPSc. These data provide information on the mechanism of replication and toxicity by PrPSc, and evoke predictable and therapeutically amenable ways of modulating PrPSc load.

{dagger}These authors contributed equally to this work.

Address correspondence to: Neena Singh (neena.singh{at}case.edu)




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