Rare Enzyme Mutation Unveils New Insights into Dementia’s Triggers

A recent study led by researchers from Helmholtz Munich has unveiled a crucial link between a rare enzyme mutation and the onset of early dementia. The investigation focused on the enzyme glutathione peroxidase 4 (GPX4), which plays a vital role in protecting neurons from damage. A specific genetic mutation, known as the R152H mutation, compromises this protective mechanism, allowing harmful molecules to inflict damage on neuronal membranes, potentially leading to early-onset dementia.

The findings, published on December 9, 2025, in the journal Cell, shed light on how GPX4 operates within neurons to prevent a form of cell death known as ferroptosis. Prof. Marcus Conrad, Director of the Institute of Metabolism and Cell Death at Helmholtz Munich and Chair of Translational Redox Biology at the Technical University of Munich (TUM), led the research team that explored this phenomenon.

The study highlights that when GPX4 functions correctly, a small structural feature, described as a “fin,” is integrated into the inner surface of neuronal membranes. This fin allows the enzyme to neutralize lipid peroxides—harmful molecules that can damage cells. In individuals with the R152H mutation, this fin is improperly shaped, preventing GPX4 from anchoring itself in the membrane effectively. As a result, lipid peroxides accumulate, leading to membrane vulnerability and triggering neuronal death.

To investigate the mutation’s effects, researchers began with three children in the United States diagnosed with an extremely rare form of early childhood dementia. All three exhibited the same alteration in the GPX4 gene, identified as the R152H mutation. The team utilized cells from one affected child, reverting them to a stem-cell-like state to study the mutation’s impacts. These stem cells were then employed to cultivate cortical neurons and three-dimensional brain-like structures known as brain organoids.

To gain a broader understanding, researchers introduced the R152H variant into a mouse model, which allowed for targeted modification of the GPX4 enzyme in specific types of nerve cells. The mice developed notable motor problems, experienced significant neuronal loss in the cerebral cortex and cerebellum, and displayed pronounced neuroinflammatory responses. These symptoms closely mirrored the conditions observed in the affected children and reflected patterns typical of neurodegenerative diseases.

The research team also conducted protein level analyses and discovered shifts similar to those documented in Alzheimer’s disease. Many proteins that fluctuate in Alzheimer’s patients exhibited comparable changes in the mice lacking functional GPX4. This connection suggests that ferroptotic stress may play a role not only in this rare form of childhood dementia but also in more prevalent dementia-related disorders.

Dr. Svenja Lorenz, a co-author of the study, remarked, “Our data indicate that ferroptosis can be a driving force behind neuronal death—not just a side effect.” Traditionally, dementia research has concentrated on amyloid beta plaques in the brain. The current findings suggest the necessity to reassess the damage to cell membranes, which may trigger the degenerative processes associated with dementia.

Initial tests indicate that blocking ferroptosis can mitigate cell death caused by the loss of GPX4 in both cell cultures and mouse models. Dr. Tobias Seibt, a nephrologist at LMU University Hospital Munich and co-first author, noted, “This is an important proof of principle, but it is not yet a therapy.” Dr. Adam Wahida, another co-author, added, “In the long term, we can envision genetic or molecular strategies to stabilize this protective system. However, our work remains firmly within the realm of basic research for now.”

This significant project is the result of a long-term scientific collaboration encompassing genetics, structural biology, stem cell research, and neuroscience. Over the years, contributions from numerous researchers around the world have advanced the understanding of complex diseases. Prof. Conrad emphasized the importance of sustained funding for basic research and international multidisciplinary teams, stating, “It has taken us almost 14 years to link a yet-unrecognized small structural element of a single enzyme to a severe human disease.”

These findings offer a new perspective on the mechanisms underlying dementia and open avenues for future research that could lead to potential therapeutic strategies.