title: A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein.
abstract: 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.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.|Dulbecco Telethon Institute, Laboratory of Prions and Amyloids, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Massignan
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cimini
authors.affiliation: Dulbecco Telethon Institute, Laboratory of Prions and Amyloids, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stincardini
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Milica
authors.initials: M
authors.lastname: Cerovic
authors.affiliation: Department of Food Safety and Veterinary Health, Istituto Superiore di Sanitá, 00161 Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Vanni
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.|Dulbecco Telethon Institute, Laboratory of Prions and Amyloids, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Saioa R
authors.initials: SR
authors.lastname: Elezgarai
authors.affiliation: CIC bioGUNE, Parque tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moreno
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Stravalaci
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Negro
authors.affiliation: Dulbecco Telethon Institute, Laboratory of Prions and Amyloids, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Sangiovanni
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Restelli
authors.affiliation: Department of Food Safety and Veterinary Health, Istituto Superiore di Sanitá, 00161 Rome, Italy.
authors.forename: Geraldina
authors.initials: G
authors.lastname: Riccardi
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: CIC bioGUNE, Parque tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.|IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Bizkaia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.|Department of Pharmacological and Biomolecular Sciences, Milan University, 20133 Milan Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
authors.affiliation: Department of Food Safety and Veterinary Health, Istituto Superiore di Sanitá, 00161 Rome, Italy.
authors.forename: Romolo
authors.initials: R
authors.lastname: Nonno
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.|Department of Food Safety and Veterinary Health, Istituto Superiore di Sanitá, 00161 Rome, Italy.|Dulbecco Telethon Institute, Laboratory of Prions and Amyloids, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Biasini
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008665:Metalloporphyrins / Q000737:chemistry* / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011166:Porphyrins; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072002:Prion Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D045725:Tetrapyrroles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D008665:Metalloporphyrins; D011166:Porphyrins; D018621:PrPC Proteins; D000072002:Prion Proteins; D011994:Recombinant Proteins; D045725:Tetrapyrroles; C092399:meso-tetrakis(1-methyl-4-pyridiniumyl)porphyrin