A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein

Tania Massignan, Sara Cimini, Claudia Stincardini, Milica Cerovic, Ilaria Vanni, Saioa R. Elezgarai, Jorge Moreno, Matteo Stravalaci, Alessandro Negro, Valeria Sangiovanni, Elena Restelli, Geraldina Riccardi, Marco Gobbi, Joaquín Castilla, Tiziana Borsello, Romolo Nonno, Emiliano Biasini

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Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrP C) into PrP Sc, a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrP Sc is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrP C may provide an opportunity to overcome these problems. PrP C ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrP C, and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrP C -related toxic activities, including the channel-forming ability of a PrP mutant, and the PrP C -dependent synaptotoxicity of amyloid-β (Aβ) oligomers, which are associated with Alzheimer € s Disease. These results demonstrate that molecules binding to PrP C may produce a dual effect of blocking prion replication and inhibiting PrP C -mediated toxicity.

Original languageEnglish
Article number23180
JournalScientific Reports
Publication statusPublished - Mar 15 2016

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    Massignan, T., Cimini, S., Stincardini, C., Cerovic, M., Vanni, I., Elezgarai, S. R., Moreno, J., Stravalaci, M., Negro, A., Sangiovanni, V., Restelli, E., Riccardi, G., Gobbi, M., Castilla, J., Borsello, T., Nonno, R., & Biasini, E. (2016). A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein. Scientific Reports, 6, [23180]. https://doi.org/10.1038/srep23180