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

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

Lorenz, Svenja M; Wahida, Adam; Bostock, Mark J; Seibt, Tobias; Santos Dias Mourão, André; Levkina, Anastasia; Trümbach, Dietrich; Soudy, Mohamed; Emler, David; Rothammer, Nicola; Woo, Marcel S; Sonner, Jana K; Novikova, Mariia; Henkelmann, Bernhard; Aldrovandi, Maceler; Kaemena, Daniel F; Mishima, Eikan; Vermonden, Perrine; Zong, Zhi; Cheng, Deng; Nakamura, Toshitaka; Ito, Junya; Doll, Sebastian; Proneth, Bettina; Bürkle, Erika; Rizzollo, Francesca; Escamilla Ayala, Abril; Napolitano, Valeria;...     »

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.      «

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...     »