Single enzyme mutation reveals a hidden trigger in dementia

Their findings center on the selenoenzyme glutathione peroxidase 4 (GPX4), which is essential for preventing this type of cell damage. A single genetic change that affects GPX4 disrupts a previously unrecognized feature of the enzyme's function. In children who inherit this mutation, the result is a severe form of early-onset dementia. When GPX4 works properly, it positions a short protein loop -- described as a "fin" -- inside the inner surface of the neuronal membrane. This allows GPX4 to neutralize lipid peroxides, harmful molecules that would otherwise damage the membrane.

How a Tiny Protein "Fin" Protects Neurons

"GPX4 is a bit like a surfboard," says Conrad. "With its fin immersed into the cell membrane, it rides along the inner surface and swiftly detoxifies lipid peroxides as it goes." In children with early-onset dementia, a point mutation reshapes this fin-like loop. The altered enzyme can no longer insert itself into the membrane correctly, leaving lipid peroxides free to accumulate. When this happens, the membrane becomes vulnerable, ferroptosis is triggered, the cell ruptures, and neurons are lost.

The research began with three children in the United States who have an extremely rare form of early childhood dementia. All three share the same alteration in the GPX4 gene, identified as the R152H mutation. Scientists used cells from one affected child and reverted them to a stem-cell-like state to investigate the mutation's effects. These stem cells were then used to grow cortical neurons and three-dimensional brain-like structures known as brain organoids.

Evidence From Mouse Models and Protein Analysis

To explore the mutation at the level of the whole organism, the team introduced the R152H variant into a mouse model. This allowed them to modify the GPX4 enzyme in specific types of nerve cells. The mice gradually developed marked motor problems, experienced significant neuron loss in the cerebral cortex and cerebellum, and showed strong neuroinflammatory responses. These findings closely matched what had been observed in the affected children and resembled patterns seen in neurodegenerative conditions.

The researchers also examined how protein levels changed in the experimental model. They found shifts very similar to those documented in Alzheimer's disease. Many proteins that increase or decrease in Alzheimer's patients showed the same disruptions in mice without functional GPX4. This pattern indicates that ferroptotic stress may be involved not only in this rare childhood condition, but also in more common dementia-related disorders.

Rethinking the Origins 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. "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 the mouse model. "This is an important proof of principle, but it is not yet a therapy," explains Dr. Tobias Seibt, nephrologist at LMU University Hospital Munich and co-first author. According to Dr. Adam Wahida, also a first author, "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 Crucial Molecular Clue

The project reflects a scientific collaboration that has expanded over many years, involving genetics, structural biology, stem cell research, and neuroscience, with contributions from several dozen researchers at institutions around the world. "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 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."