​Karlin Wurlitzer,¹ Chi Ma,¹ Lance Nunes,¹ Fukun W. Hoffmann,¹ Matthew W. Pitts¹

¹ Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaiʻi

Selenoprotein I (SELENOI) is a crucial enzyme for phospholipid synthesis in oligodendrocytes. It catalyzes the production of plasmenyl-phosphatidylethanolamine (plasmenyl-PE), a key component of myelin which protects and insulates neuronal axons. Crucially, myelin-producing oligodendrocytes also have the highest concentration of iron. Iron is a vital metal cofactor due to its aptitude for redox reactions, but this propensity also predisposes it to generating reactive oxygen species (ROS) via Fenton reactions. Additionally, iron accumulation is an intracellular signal for regulated cell death via ferroptosis, an iron-dependent phospholipid peroxidation process. In the brain, iron dysregulation in various cell types has been implicated in neurodegenerative disorders such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and hereditary spastic paraplegia (HSP). SELENOI has been negatively associated with ferroptosis; mechanistically, plasmenyl-PE contains a vinyl ether bond that may be sacrificially oxidized to protect against lipid peroxidation. Due to this association, we used a brain-specific mouse knockout (KO) model to elucidate the effects of SELENOI on iron metabolism in order to understand how redox homeostasis might play a role in iron-dependent neurodegeneration.