Journal Article

DKFZ-2025-02774

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.

Lorenz, S. M. ; 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-Adamska, M. ; Gaussmann, S. ; Merl-Pham, J. ; Hauck, S. ; Pertek, A. ; Orschmann, T. ; van San, E. ; Vanden Berghe, T. ; Hass, D. ; Maida, A. ; Frenz, J.DKFZ* ; Pedrera, L. ; Dolga, A. ; Kraiger, M. ; Hrabé de Angelis, M. ; Fuchs, H. ; Ebert, G. ; Lenberg, J. ; Friedman, J. ; Scale, C. ; Agostinis, P. ; Zimprich, A. ; Vogt-Weisenhorn, D. ; Garrett, L. ; Hölter, S. M. ; Wurst, W. ; Glaab, E. ; Lewerenz, J. ; Popper, B. ; Sieben, C. ; Steinacker, P. ; Zischka, H. ; Garcia-Saez, 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.DKFZ* ; Popowicz, G. M. ; Conrad, M.

2026
Cell Press [Cambridge, Mass.]

Abstract: 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.

Keyword(s): Alzheimer’s disease ; GPX4 ; SSMD ; Sedaghatian type ; cell death ; ferroptosis ; neurodegeneration ; neuroinflammation ; spondylometaphyseal dysplasia

Note: 2026 Jan 8;189(1):287-306.e35

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Contributing Institute(s):

1. KKE Pädiatrische Leukämie (A400)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 60 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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