Researchers from the Helmholtz Center Munich, the Technical University of Munich, and the University Hospital of LMU Munich have discovered a mechanism that protects nerve cells from premature cell death, known as ferroptosis. The study provides the first molecular evidence that ferroptosis can trigger neurodegeneration in the human brain. These findings open up new avenues for the development of future therapies – particularly for severe, early-onset childhood dementia.
The enzyme that protects nerve cells
Why do neurons die off in dementia – and can this process be slowed down? An international team led by Prof. Marcus Conrad, Director of the Institute for Metabolism and Cell Death at the Helmholtz Center Munich and holder of the Chair of Translational Redox Biology at the Technical University of Munich (TUM), now describes in Cell how neurons protect themselves from ferroptotic cell death.
Central to this defense mechanism is the selenoenzyme glutathione peroxidase 4 (GPX4). A single mutation in the gene encoding GPX4 can impair a crucial, previously unknown component of the enzyme's function. In affected children, this leads to severe, early-onset dementia. In its fully functional state, GPX4 inserts a short protein loop – a kind of “fin” – into the inner side of the neuronal cell membrane, allowing the enzyme to neutralize harmful substances called lipid peroxides.
Surfing along the cell membrane
“GPX4 is comparable to a surfboard,” explains Conrad. “With its fin penetrating the cell membrane, it glides along the inner surface, rapidly detoxifying lipid peroxides in the process.” A point mutation found in children with early-onset dementia alters this fin-like protein loop: the enzyme can no longer properly insert itself into the membrane and fulfill its cell-protective function. Lipid peroxides can then damage the membrane, triggering ferroptosis and cell rupture, and the neurons die.
The study began with three children in the USA suffering from an extremely rare form of early-onset dementia. All three have the same alteration in the GPX4 gene, known as the R152H mutation. Using cell samples from an affected child, the researchers were able to investigate the effects of the mutation in more detail and revert the cells to a stem-cell-like state. From these reprogrammed stem cells, they subsequently generated cortical neurons and three-dimensional tissue structures that resemble early brain tissue – so-called brain organoids.
Lab findings confirm: Without functional GPX4, dementia develops.
To understand the processes in the overall organism, the team introduced the R152H mutation into a mouse model, thereby specifically altering the GPX4 enzyme in various nerve cell types. As a result of impaired GPX4 function, the animals gradually developed severe motor deficits, accompanied by the death of neurons in the cerebral cortex and cerebellum, as well as pronounced neuroinflammatory reactions in the brain – a pattern that closely resembles observations in affected children and is highly comparable to profiles of neurodegenerative diseases.
In parallel, the researchers analyzed which proteins in the animal model changed in their quantity. They observed a pattern that was strikingly similar to that in Alzheimer's patients: numerous proteins whose quantity is increased or decreased in Alzheimer's were also dysregulated in mice without functional GPX4. This suggests that ferroptotic stress may play a role not only in this rare, early-onset disease but possibly also in more common forms of dementia.
DOI
10.1016/j.cell.2025.11.014
