A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis
Svenja Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Chen, Toshitaka Nakamura, Junya Ito, Sebastian Doll, Bettina Proneth, Erika Bürkle, Francesca Rizzollo, Abril Escamilla‐Ayala, Valeria Napolitano, Marta Kolonko, Stefan Gaussmann, Juliane Merl‐Pham, Stefanie M. Hauck, Anna Pertek, Tanja Orschmann, Emily Van San, Tom Vanden Berghe, Daniela Hass, Adriano Maida, J. Frenz, Lohans Pedrera, Amalia M. Dolga, Markus Kraiger, Martin Hrabě de Angelis, Helmut Fuchs, Gregor Ebert, Jerica Lenberg, Jennifer Friedman, Carolin Scale, Patrizia Agostinis, Annemarie Zimprich, Daniela M. Vogt Weisenhorn, Lillian Garrett, Sabine M. Hölter, Wolfgang Wurst, Enrico Glaab, Jan Lewerenz, Bastian Popper, Christian Sieben, Petra Steinacker, Hans Zischka, Ana J. García‐Sáez, Anna Tietze, Sanath Kumar Ramesh, Scott Ayton, Michelle Vincendeau, Manuel A. Friese, Kristen Wigby, Michael Sattler, Matthias Mann, Irina Ingold, Ashok Kumar Jayavelu, Grzegorz M. Popowicz, Marcus Conrad
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 GPX4 R152H 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.