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Vol. 18, Issue 9, 3302-3312, September 2007

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

Subhabrata Basu^*,, Maradumane L. Mohan^*,, Xiu Luo^*,, Bishwajit Kundu, Qingzhong Kong^*, and Neena Singh^*

*Department of Pathology, Case Western Reserve University, Cleveland, OH 44106; and Department of Biochemical Engineering and Biotechnology, The Indian Institute of Technology, New Delhi, India 110016

Submitted April 9, 2007; Revised May 31, 2007; Accepted June 4, 2007
Monitoring Editor: Jonathan Weissman

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

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

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

Abbreviations used: CJDH, sCJD brain homogenate; DAB, 3,3'-diaminobenzidine; NH, normal brain homogenate; P₂I, high-speed detergent-insoluble pellet from mock and FeCl₂-exposed cells; P₂II, high-speed detergent-insoluble pellet from P₂I-exposed cells; ScH, scrapie-infected mouse brain homogenate.

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