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Petruzzelli, R.* ; Catalano, F.* ; Crispino, R.* ; Polishchuk, E.V.* ; Elia, M.* ; Masone, A.* ; Lavigna, G.* ; Grasso, A.* ; Battipaglia, M.* ; Sepe, L.V.* ; Akdogan, B. ; Reinold, Q.* ; Del Prete, E.* ; Carrella, D.* ; Torella, A.* ; Nigro, V.* ; Caruso, E.* ; Innocenti, N.* ; Biasini, E.* ; Puchkova, L.V.* ; Indrieri, A.* ; Ilyechova, E.Y.* ; Piccolo, P.* ; Zischka, H. ; Chiesa, R.* ; Polishchuk, R.S.*

Prion protein promotes copper toxicity in Wilson disease.

Nat. Commun. 16:1468 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Gene-expression; Differential Expression; Endocytosis; Accumulation; Codon-129; Prp
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 1468 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOX)
Grants Russian Science Foundation
Telethon Italy
European Joint Project - Rare Diseases
Italian Ministry of Health
AIRC, Italy
Italian National Wilson Disease Organization
CNR/RFBR (Russian Foundation for Basic Research) Collaboration Program, Italy
Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)