Researchers in a recent breakthrough have identified hidden enzyme mutations behind the cases of dementia, leading to cell death due to ferroptosis.
A new study led by Prof. Marcus Conrad from Helmholtz Munich and TUM explains how nerve cells can protect themselves against neuron death. At the heart of their research is the essential selenoenzyme glutathione peroxidase 4 (GPX4).
This is evident from findings published in the journal Cell, GPX4 acts as a protective shield for nerve cells. Normally, the enzyme works by inserting a short protein loop into the inner surface of the neuronal membrane, allowing GPX4 to detoxify lipid peroxides and harmful molecules and protect against cell death.
“GPX4 looks a bit like a surfboard. With its fin immersed in the cell membrane, it glides along the inner surface, quickly detoxifying lipid peroxides along the way,” says Conard.
A point mutation in GPX4 disrupts its function and causes a severe form of early dementia in children.
As a result, the mutated enzyme fails to insert itself properly into the membrane, leading to accumulation of lipid peroxides. As a result of accumulation, the membrane becomes susceptible to ferroptosis, the cells rupture and the nerves become damaged.
The research also offers opportunities for future therapies to slow the process. Blocking ferroptosis may slow cell death caused by GPX4 loss, according to early tests.
The researchers are pursuing genetic and molecular strategies to protect the GPX4 system and prevent ferroptosis.
