Prion protein promotes copper toxicity in Wilson disease
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.
Article Details
Authors (26)
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
Department of Cellular, Computational and Integrative Biology, University of Trento
Ludmila V. Puchkova
Alessia Indrieri
Telethon Institute of Genetics and Medicine
Ekaterina Y. Ilyechova
Pasquale Piccolo
Hans Zischka
Roberto Chiesa
Roman S. Polishchuk