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,...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56740-x |
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| author | 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 |
| author_facet | 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 |
| author_sort | Raffaella Petruzzelli |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d35cee64f23d406bbeb98611c1be8321 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d35cee64f23d406bbeb98611c1be83212025-02-09T12:44:59ZengNature PortfolioNature Communications2041-17232025-02-0116111810.1038/s41467-025-56740-xPrion protein promotes copper toxicity in Wilson diseaseRaffaella Petruzzelli0Federico Catalano1Roberta Crispino2Elena V. Polishchuk3Mariantonietta Elia4Antonio Masone5Giada Lavigna6Anna Grasso7Maria Battipaglia8Lucia Vittoria Sepe9Banu Akdogan10Quirin Reinold11Eugenio Del Prete12Diego Carrella13Annalaura Torella14Vincenzo Nigro15Enrico Caruso16Nicole Innocenti17Emiliano Biasini18Ludmila V. Puchkova19Alessia Indrieri20Ekaterina Y. Ilyechova21Pasquale Piccolo22Hans Zischka23Roberto Chiesa24Roman S. Polishchuk25Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Department of Neuroscience, Laboratory of Prion Neurobiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCSDepartment of Neuroscience, Laboratory of Prion Neurobiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCSDepartment of Neuroscience, Laboratory of Prion Neurobiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCSTelethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental HealthInstitute of Toxicology and Environmental Hygiene, Technical University Munich School of Medicine and HealthTelethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Department of Biotechnology and Life Sciences, University of InsubriaDepartment of Cellular, Computational and Integrative Biology, University of TrentoDepartment of Cellular, Computational and Integrative Biology, University of TrentoDepartment of Molecular Genetics, Research Institute of Experimental MedicineTelethon Institute of Genetics and Medicine (TIGEM)Department of Molecular Genetics, Research Institute of Experimental MedicineTelethon Institute of Genetics and Medicine (TIGEM)Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental HealthDepartment of Neuroscience, Laboratory of Prion Neurobiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCSTelethon Institute of Genetics and Medicine (TIGEM)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.https://doi.org/10.1038/s41467-025-56740-x |
| spellingShingle | 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 Prion protein promotes copper toxicity in Wilson disease Nature Communications |
| title | Prion protein promotes copper toxicity in Wilson disease |
| title_full | Prion protein promotes copper toxicity in Wilson disease |
| title_fullStr | Prion protein promotes copper toxicity in Wilson disease |
| title_full_unstemmed | Prion protein promotes copper toxicity in Wilson disease |
| title_short | Prion protein promotes copper toxicity in Wilson disease |
| title_sort | prion protein promotes copper toxicity in wilson disease |
| url | https://doi.org/10.1038/s41467-025-56740-x |
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