Selenoprotein I deficiency disrupts iron homeostasis in brain

Selenoprotein I (SELENOI) is an essential enzyme for phospholipid synthesis that catalyzes the production of plasmenyl-phosphatidylethanolamine (plasmenyl-PE), a key component of myelin that protects and insulates axons. We recently generated a mouse model of central nervous system-restricted SELENOI deficiency that recapitulates features observed in humans with rare loss-of-function SELENOI gene mutations such as motor deficits, diminished plasmenyl-PE, and hypomyelination. Crucially, myelin-producing oligodendrocytes have the highest concentration of iron among cell types in brain. Iron is a vital metal cofactor due to its contribution to redox reactions, but this property also predisposes it to generating reactive oxygen species via Fenton reactions. Moreover, an excess of redox-active iron promotes lipid peroxidation and increases susceptibility to cell death via ferroptosis. In this report, we show that SELENOI deficiency in mouse brain leads to ferroptosis in white matter tracts and promotes iron accumulation. These alterations are accompanied by oligodendrocyte proliferation and elevated numbers of ferritin-positive microglia in affected regions. Overall, our findings detail an intermittent cycle of oligodendrocyte death and proliferation that occurs when SELENOI is absent from the brain, resulting in accelerated iron accrual.