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Peng, H. ; Pfeiffer, S. ; Varynskyi, B. ; Qiu, M. ; Srinark, C. ; Jin, X.* ; Zhang, X. ; Williams, K.* ; Groveman, B.R.* ; Foliaki, S.T.* ; Race, B.* ; Thomas, T.* ; Chen, C.* ; Müller, C. ; Kovács, K.J.* ; Arzberger, T.* ; Momma, S.* ; Haigh, C.L.* ; Schick, J.A.

Prion-induced ferroptosis is facilitated by RAC3.

Nat. Commun. 16:5385 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Prions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPC creates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPC and infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPC initially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Endoplasmic-reticulum Stress; Induced Oxidative Stress; Cell-death; Protein; Accumulation; Propagation; Expression; Resistant; Transport; Toxicity
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 16, Heft: 1, Seiten: , Artikelnummer: 5385 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
Research Unit BioGeoChemistry and Analytics (BGC)
POF Topic(s) 30203 - Molecular Targets and Therapies
30202 - Environmental Health
Forschungsfeld(er) Enabling and Novel Technologies
Environmental Sciences
PSP-Element(e) G-509800-005
G-504800-001
Förderungen National Institutes of Health (NIAID)
Undergraduates Training Program for Innovation and Entrepreneurship of Hainan Province
Specific Research Fund of the Innovation Platform for Academicians of Hainan Province
Helmholtz Center Munich
DFG
German Research Foundation (DFG)
Innovation Platform for Academicians of Hainan Province
Deutsche Forschungsgemeinschaft (German Research Foundation)
DOI 10.1038/s41467-025-60793-3
WOS ID 001517178700012
Scopus ID 105008881184
PubMed ID 40562790
Erfassungsdatum 2025-06-27
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