Scientists have recognized a small flaw within the enzyme GPX4 that stops neurons from defending themselves. This mutation, present in youngsters with a uncommon type of early dementia, disrupts a tiny loop the enzyme makes use of to guard cell membranes.
Lab and animal research confirmed widespread neuron loss when GPX4 fails. The outcomes counsel a deeper connection between this course of and different kinds of dementia.
Why Neurons Die in Dementia
Why do neurons die in dementia – and may this course of be slowed down? A world analysis workforce led by Prof. Marcus Conrad, Director of the Institute of Metabolism and Cell Demise at Helmholtz Munich and Chair of Translational Redox Biology on the Technical College of Munich (TUM), stories in Cell how neurons use a built-in system to guard themselves from ferroptotic cell loss of life.
Central to this safety is the selenoenzyme glutathione peroxidase 4 (GPX4). A single mutation within the gene accountable for GPX4 disrupts a beforehand unknown a part of the enzyme’s operate. In youngsters who inherit this mutation, the result’s extreme early-onset dementia. Underneath regular circumstances, GPX4 inserts a brief protein loop – described as a “fin” – into the inside aspect of the neuronal membrane. This enables the enzyme to neutralize lipid peroxides, dangerous molecules that may in any other case harm the cell.
How the GPX4 “Fin” Shields Neurons
“GPX4 is a bit like a surfboard,” says Conrad. “With its fin immersed into the cell membrane, it rides alongside the inside floor and swiftly detoxifies lipid peroxides because it goes.” In youngsters with early-onset dementia, a degree mutation alters this fin-like loop. The modified construction prevents GPX4 from anchoring into the membrane, leaving lipid peroxides to build up. When these molecules construct up, they weaken the membrane, set off ferroptosis, and in the end trigger neurons to rupture and die.
The venture started with three youngsters in america who’ve an especially uncommon type of early childhood dementia. All three share the identical mutation within the GPX4 gene, referred to as R152H. Utilizing cells from one affected little one, the workforce reprogrammed the samples right into a stem-cell-like state. These stem cells had been then used to create cortical neurons and three-dimensional buildings resembling early mind tissue, referred to as mind organoids.
Proof From Mouse Fashions and Protein Evaluation
To see how the mutation impacts an entire organism, the researchers launched the R152H variant right into a mouse mannequin. This allowed them to change GPX4 operate particularly in several types of nerve cells. As GPX4 turned impaired, the mice slowly developed critical motor issues, skilled neuron loss within the cerebral cortex and cerebellum, and confirmed sturdy neuroinflammatory reactions. These options intently matched what was seen within the affected youngsters and resembled patterns typical of neurodegenerative illnesses.
On the similar time, the workforce examined modifications in protein ranges within the experimental mannequin. Many proteins that improve or lower in Alzheimer’s disease showed similar changes in mice lacking functional GPX4. This overlap suggests that ferroptotic stress may contribute not only to this rare childhood disorder, but also to more widespread forms of dementia.
Rethinking the Roots of Dementia
“Our data indicate that ferroptosis can be a driving force behind neuronal death – not just a side effect,” says Dr. Svenja Lorenz, one of the first authors of the study. “Until now, dementia research has often focused on protein deposits in the brain, so-called amyloid ß plaques. We are now putting more emphasis on the damage to cell membranes that sets this degeneration in motion in the first place.”
Early tests show that blocking ferroptosis can slow the cell death caused by loss of GPX4 in both cell cultures and mice. “This is an important proof of principle, but it is not yet a therapy,” says Dr. Tobias Seibt, nephrologist at LMU University Hospital Munich and co-first author. Dr. Adam Wahida, also a first author of the study, adds: “In the long term, we can imagine genetic or molecular strategies to stabilize this protective system. For now, however, our work clearly remains in the realm of basic research.”
Long-Term Collaboration Reveals a Key Molecular Detail
The findings come from a research network built over many years, combining genetics, structural biology, stem cell research, and neuroscience across multiple international sites.
“It has taken us almost 14 years to link a yet-unrecognized small structural element of a single enzyme to a severe human disease,” says Marcus Conrad. “Projects like this vividly demonstrate why we need long-term funding for basic research and international multidisciplinary teams if we are to truly understand complex diseases such as dementia and other neurodegenerative disease conditions.”
Reference: “A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis” by Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias 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 Cheng, Toshitaka Nakamura, Junya Ito, Sebastian Doll, Bettina Proneth, Erika Bürkle, Francesca Rizzollo, Abril Escamilla Ayala, Valeria Napolitano, Marta Kolonko-Adamska, Stefan Gaussmann, Juliane Merl-Pham, Stefanie Hauck, Anna Pertek, Tanja Orschmann, Emily van San, Tom Vanden Berghe, Daniela Hass, Adriano Maida, Joris M. Frenz, Lohans Pedrera, Amalia Dolga, Markus Kraiger, Martin Hrabé de Angelis, Helmut Fuchs, Gregor Ebert, Jerica Lenberg, Jennifer Friedman, Carolin Scale, Patrizia Agostinis, Annemarie Zimprich, Daniela Vogt-Weisenhorn, Lillian Garrett, Sabine M. Hölter, Wolfgang Wurst, Enrico Glaab, Jan Lewerenz, Bastian Popper, Christian Sieben, Petra Steinacker, Hans Zischka, Ana J. Garcia-Saez, 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 and Marcus Conrad, 4 December 2025, Cell.
DOI: 10.1016/j.cell.2025.11.014
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.
