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Lorenz, S. ; Wahida, A. ; Bostock, M.J. ; Seibt, T. ; Santos Dias Mourão, A. ; Levkina, A. ; Trümbach, D. ; Soudy, M.* ; Emler, D. ; Rothammer, N.* ; Woo, M.S.* ; Sonner, J.K.* ; Novikova, M. ; Henkelmann, B. ; Aldrovandi, M. ; Kaemena, D.F. ; Mishima, E. ; Vermonden, P. ; Zong, Z. ; Cheng, D. ; Nakamura, T. ; Ito, J. ; Doll, S. ; Proneth, B. ; Bürkle, E. ; Rizzollo, F.* ; Escamilla Ayala, A.* ; Napolitano, V. ; Kolonko, M. ; Gaussmann, S. ; Merl-Pham, J. ; Hauck, S.M. ; Pertek, A. ; Orschmann, T. ; Van San, E.* ; Vanden Berghe, T.* ; Hass, D, ; Maida, A. ; Frenz, J.M.* ; Pedrera, L.* ; Dolga, A.M.* ; Kraiger, M. ; Hrabě de Angelis, M. ; Fuchs, H. ; Ebert, G. ; Lenberg, J.* ; Friedman, J.* ; Scale, C.* ; Agostinis, P.* ; Zimprich, A. ; Vogt Weisenhorn, D.M. ; Garrett, L. ; Hölter, S.M. ; Wurst, W. ; Glaab, E.* ; Lewerenz, J.* ; Popper, B.* ; Sieben, C.* ; Steinacker, P.* ; Zischka, H. ; García-Sáez, A.J.* ; Tietze, A.* ; Ramesh, S.K.* ; Ayton, S.* ; Vincendeau, M. ; Friese, M.A.* ; Wigby, K.* ; Sattler, M. ; Mann, M.* ; Ingold, I. ; Jayavelu, A.K.* ; Popowicz, G.M. ; Conrad, M.

A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.

Cell, DOI: 10.1016/j.cell.2025.11.014 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Alzheimer’s Disease ; Gpx4 ; Ssmd ; Sedaghatian Type ; Cell Death ; Ferroptosis ; Neurodegeneration ; Neuroinflammation ; Spondylometaphyseal Dysplasia
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Institute of Structural Biology (STB)
Institute of Virology (VIRO)
CF Metabolomics & Proteomics (CF-MPC)
Institute of Diabetes and Cancer (IDC)
Institute of Experimental Genetics (IEG)
Institute of Developmental Genetics (IDG)
Institute of Molecular Toxicology and Pharmacology (TOX)