Healthcare (Commonwealth Union) – German Researchers from Helmholtz Munich, the Technical University of Munich, and LMU University Hospital Munich have identified a protective process that shields nerve cells from an early type of cell death called ferroptosis. Their research offers the first molecular proof that ferroptosis can actively contribute to neurodegeneration in the human brain. The discovery could pave the way for new treatment strategies — especially for rare forms of childhood dementia that appear very early in life.
To explore the causes of neurons deteriorating in dementia, and if this this decline be slowed needed to be explored. An international research group led by Prof. Marcus Conrad, who heads the Institute of Metabolism and Cell Death at Helmholtz Munich and serves as Chair of Translational Redox Biology at the Technical University of Munich (TUM), explains in Cell how nerve cells defend themselves against ferroptotic damage.
At the core of this protective system is a selenoenzyme called glutathione peroxidase 4 (GPX4). A single genetic change affecting GPX4 can interfere with a key, previously unrecognized aspect of how the enzyme works, leading to severe early-onset dementia in children who carry this mutation. When GPX4 functions normally, it uses a tiny protein loop — like a small “fin” — to anchor itself inside the neuronal cell membrane. This allows the enzyme to break down harmful lipid peroxides before they can injure the cell.
“GPX4 is a bit like a surfboard,” explained Conrad. “With its fin immersed into the cell membrane, it rides along the inner surface and swiftly detoxifies lipid peroxides as it goes.” Researchers described it as a single point mutation seen in children with early-onset dementia adjusts this fin-like protein loop: the enzyme is then unable to insert into the membrane properly to carry out its cell-defensive function. Lipid peroxides are then to damage the membrane, triggering ferroptosis and cell rupture, and the neurons die.
The investigation began with three U.S. children diagnosed with an exceptionally rare type of early childhood dementia. All of them share the same alteration in the GPX4 gene, called the R152H mutation. Using cells taken from one of the children, the research team examined how this mutation affects cellular processes. They first reverted the cells into an induced stem-cell-like state and then used them to create cortical neurons and three-dimensional clusters of tissue that mimic early brain development, known as brain organoids.
To explore the mutation’s effects in a living organism, the scientists engineered the R152H variant into a mouse model, specifically modifying the GPX4 enzyme in various types of neurons. Because GPX4 function was compromised, the mice gradually showed serious coordination and movement problems. Their brains exhibited widespread neuron loss in the cortex and cerebellum, along with strong inflammatory reactions—closely matching what has been seen in the affected children and mirroring patterns typical of neurodegenerative conditions.
At the same time, the team studied how protein levels shift in this model. They noticed changes that closely resembled those documented in Alzheimer’s disease: many proteins that rise or fall in Alzheimer’s patients were similarly altered in mice without working GPX4. These findings indicate that ferroptotic stress might contribute not only to this ultra-rare childhood disorder, but also to more widespread types of dementia.
“Our data indicate that ferroptosis can be a driving force behind neuronal death – not just a side effect,” explained Dr. Svenja Lorenz, who was among the first authors of the research. “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.”
