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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)

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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 PrP^C, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrP^C, 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 PrP^C 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 PrP^C 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 PrP^C 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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Endoplasmic-reticulum Stress; Induced Oxidative Stress; Cell-death; Protein; Accumulation; Propagation; Expression; Resistant; Transport; Toxicity

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 16, Issue: 1, Article Number: 5385

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Signaling and Translation (SAT)
Research Unit BioGeoChemistry and Analytics (BGC)

Grants 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)