Prion protein promotes copper toxicity in Wilson disease

Prion protein promotes copper toxicity in Wilson disease

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,...

Full description

Saved in:
Bibliographic Details
Main Authors: 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, Roman S. Polishchuk
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56740-x
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2041-1723

Similar Items