Glutathione peroxidase 4 (GPX4) is an important anti-oxidative enzyme which normally contains selenium in the form of the amino acid selenocysteine.
Mutant mice which lacked selenium in their GPX4 enzymes, failed to develop specialised brain cells called parvalbumin (PV) interneurons and consequently suffered fatal epileptic seizures within three weeks, found the research team led by the Institute of Developmental Genetics (IDG) at Helmholtz Zentrum, Munich.
“We were able to show that these neurons were lost during postnatal development, when sulphur- instead of selenium-containing GPX4 was present," commented first author, Irina Ingold.
A type of cell death called ferroptosis was responsible for this, the team also discovered.
Ferroptosis is a type of programmed cell death dependent on iron. Although its mechanism is still not fully understood, the scientists were able to demonstrate that ferroptosis is triggered by oxidative stress.
The presence of the protein selenocysteine in GPX4 appears critical in providing anti-oxidative protection of these interneurons, explained the researchers.
"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 Dr. José Pedro Friedmann Angeli. "Selenium-containing GPX4 protects these specialized neurons from oxidative stress and from ferroptotic cell death."
The PV interneurons have previously been shown to play a role in regulating excitability within the brain cortex. Neuronal hyperexcitability is recognised as a characteristic of epilepsy.
Significance
If the findings are transferable to humans, the study implies an indispensable role for selenium, suggest the researchers.
Selenium’s function in post-natal brain development may be especially important because neurons contain high amounts of polyunsaturated fatty acids (PUFAs), rendering them vulnerable to ferroptosis, suggest the scientists.
“As neurons contain a high content of PUFAs, necessary for migration and synapse formation, they are exquisitely sensitive to ferroptosis,” wrote Ingold.
Future research
Further clarification of the ferroptosis mechanism and its role in various diseases are among objectives of further work by the team.
Although ferroptosis has been shown to have a harmful effect in this study, previous in vitro cellular research suggests that ferroptosis may have a positive role to play in treatment of renal, pancreatic, ovarian and other cancers.
Source: Cell
Published online, doi: 10.1016/j.cell.2017.11.048
“Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis”
Authors: Irina Ingold, et al