Selenocysteine is an uncommon, yet close relative of cysteine (in which the thiol group is replaced with selenol) that is the defining building block of selenoproteins. However, because most of the known selenoproteins also come with cysteine-containing homologous counterparts, the actual advantage of selenium-based catalysis remains unknown. In a recent finding, a team from Helmholtz Zentrum München in Germany has uncovered a new explanatory role for selenoproteins in the mammalian nervous system.
The selenoprotein investigated in the study was the mouse GPX4, a type of glutathione peroxidase that plays a protective role in oxidative stress and ferroptotic cell death. In looking at mouse models in which this enzyme is modified, the team found that “mice with a replacement of selenium to sulfur in GPX4 did not survive for longer than three weeks due to neurological complications."
The team found a distinct subpopulation of specialized brain neurons that appear to be absent when selenium-containing GPX4 was also absent. Study first author Irina Ingold reports that “these neurons were lost during postnatal development when sulfur, instead of selenium-containing GPX4, was present.”
As concluded in the team’s recent publication in Cell, selenium-containing GPX4 exclusively ensures the neurons’ survival and prevents fatal epileptic seizures. The underlying mechanism appears to stem from selenocysteine’s exquisite resistance to irreversible overoxidation. Meanwhile, cells expressing the cysteine variant remain susceptible to peroxide-induced ferroptosis. Such oxidative stress is known to occur during high neuronal activity.
"Our study demonstrates for the first time that selenium is an essential factor for the postnatal development of a specific type of interneurons," said co-author José Pedro Friedmann Angeli. "Selenium-containing GPX4 protects these specialized neurons from oxidative stress and from ferroptotic cell death."
These findings also provide an explanation to why certain selenoproteins are essential in some organisms, such as mammals, but can be dispensable in other organisms, such as fungi and higher plants.
Image: Selenium protects a specific type of interneurons in the brain. Image courtesy of Ingold et al., Cell, 2017.