A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein

Prion diseases, which include Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI) and Gerstmann-Straussler-Scheinker (GSS) syndrome, can manifest in a sporadic, inherited or transmissible fashion. These disorders are associated with the conformational conversion of PrPC, an endogenous cell-surface glycoprotein, into PrPSc, a self-propagating, infectious protein (prion). PrPSc replicates by directly binding to PrPC, and causing its conformational rearrangement into new PrPSc molecules1. A great deal of evidence indicates that PrPSc may exist as an ensemble of conformers (referred to as prion strains), eliciting different neuropathological effects2. Prion strains represent a critical problem for treating prion diseases. In fact, several potent anti-prion compounds are strain-specific3,4,5. Moreover, acquisition of resistance to therapeutic treatments, reported in prion-infected cells and mice, has been attributed to the appearance of drug-resistant prion strains6,7. An additional confounding factor for drug discovery in prion diseases is related to the pathogenicity of PrPSc. It is becoming increasingly evident that PrPSc is not neurotoxic per se, and instead requires functional PrPC at the neuronal surface to deliver its detrimental effects8,9,10. Thus, PrPC appears to play two crucial roles in prion diseases, by passively sustaining prion replication, and actively mediating PrPSc toxicity. Analogously, several studies have shown that PrPC may act as a selective, high affinity and toxicity-transducing receptor for Aβ oligomers, which are thought to be responsible for the synaptotoxicity underlying the cognitive decline in Alzheimer’s disease11. An additional study reported that PrPC may also mediate the cytotoxicity of other β-sheet-rich protein aggregates12. These data suggest that, in addition to PrPSc, multiple disease-associated protein aggregates may use PrPC to deliver their detrimental effects. This conclusion has therapeutic relevance. Compounds targeting PrPC, and blocking its transducing activity, may provide potential benefits for prion diseases, and possibly other neurodegenerative disorders13. Various chemical classes have been reported to bind PrPC. However, a careful evaluation of data reproducibility, as well as consistency between binding affinity and biological activity, restricted the number to a few14,15. Among these, an iron tetrapyrrole derivative [Fe(III)-TMPyP, Fe(III)-meso-tetra(N-methyl-4-pyridyl)porphine] was shown to interact with the C-terminal, structured domain of PrPC, and to inhibit prion replication in vitro and in cells16,17. The compound, or highly similar porphyrins, also significantly prolonged survival in prion-infected mice18,19,20. In this study, in addition to reproducing and extend PrPC-binding and anti-prion properties of Fe(III)-TMPyP, we report unexpected evidence regarding the activity of this compound in different cell-based assays for PrPC-related toxicity.