Prion protein promotes copper toxicity in Wilson disease

• DOI: 10.1038/s41467-025-56740-x
• Publication Date: 2025-02-08T15:02:18Z
• Authors: Raffaella Petruzz...; 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. Ilye...; Pasquale Piccolo; Hans Zischka; Roberto Chiesa; Roman S. Polishchuk
• Keywords: Copper toxicity; Metallothionein; Homeostasis; Efflux; Mediator; Transport protein

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