Prion protein promotes copper toxicity in Wilson disease

Raffaella Petruzzelli, Federico Catalano, Roberta Crispino, Elena V. Polishchuk, Mariantonietta Elia, Antonio Masone, Giada Lavigna, Anna Grasso, Maria Battipaglia, Lucia Vittoria Sepe, Banu Akdogan, Quirin Reinold, Eugenio Del Prete, Diego Carrella, Annalaura Torella, Vincenzo Nigro, Enrico Caruso, Nicole Innocenti, Emiliano Biasini, Ludmila V. Puchkova, Alessia Indrieri, Ekaterina Y. Ilyechova, Pasquale Piccolo, Hans Zischka, Roberto Chiesa () and Roman S. Polishchuk ()
Additional contact information
Raffaella Petruzzelli: Telethon Institute of Genetics and Medicine (TIGEM)
Federico Catalano: Telethon Institute of Genetics and Medicine (TIGEM)
Roberta Crispino: Telethon Institute of Genetics and Medicine (TIGEM)
Elena V. Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)
Mariantonietta Elia: Telethon Institute of Genetics and Medicine (TIGEM)
Antonio Masone: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Giada Lavigna: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Anna Grasso: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Maria Battipaglia: Telethon Institute of Genetics and Medicine (TIGEM)
Lucia Vittoria Sepe: Telethon Institute of Genetics and Medicine (TIGEM)
Banu Akdogan: Helmholtz Center Munich, German Research Center for Environmental Health
Quirin Reinold: Technical University Munich School of Medicine and Health
Eugenio Del Prete: Telethon Institute of Genetics and Medicine (TIGEM)
Diego Carrella: Telethon Institute of Genetics and Medicine (TIGEM)
Annalaura Torella: Telethon Institute of Genetics and Medicine (TIGEM)
Vincenzo Nigro: Telethon Institute of Genetics and Medicine (TIGEM)
Enrico Caruso: University of Insubria
Nicole Innocenti: University of Trento
Emiliano Biasini: University of Trento
Ludmila V. Puchkova: Research Institute of Experimental Medicine
Alessia Indrieri: Telethon Institute of Genetics and Medicine (TIGEM)
Ekaterina Y. Ilyechova: Research Institute of Experimental Medicine
Pasquale Piccolo: Telethon Institute of Genetics and Medicine (TIGEM)
Hans Zischka: Helmholtz Center Munich, German Research Center for Environmental Health
Roberto Chiesa: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Roman S. Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Copper (Cu) is a vitally important micronutrient, whose balance between essential and toxic levels requires a tightly regulated network of proteins. Dysfunction in key components of this network leads to the disruption of Cu homeostasis, resulting in fatal disorders such as Wilson disease, which is caused by mutations in the hepatic Cu efflux transporter ATP7B. Unfortunately, the molecular targets for normalizing Cu homeostasis in Wilson disease remain poorly understood. Here, using genome-wide screening, we identified the cellular prion protein (PrP) as an important mediator of Cu toxicity in WD. Loss of ATP7B stimulates hepatic expression of PrP, which promotes endocytic Cu uptake, leading to toxic Cu overload. Suppression of PrP significantly reduces Cu toxicity in cell and animal models of Wilson disease. These findings highlight the critical regulatory role of PrP in copper metabolism and open new avenues for exploring the therapeutic potential of PrP suppression in Wilson disease.

Date: 2025
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DOI: 10.1038/s41467-025-56740-x

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