The role of Selenoprotein I in mitigating neurodegeneration.

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Selenoprotein I (SELENOI) is a poorly characterized enzyme that depends on adequate dietary selenium for expression and has been shown to catalyze the final reaction of the CDP-ethanolamine branch of the Kennedy pathway within the endoplasmic reticulum membrane. These pathways depend on SELENOI for efficient synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are important phospholipids in cellular membranes. Although present in various cell-types throughout the body, PE and plasmenyl PE are particularly enriched in central nervous system (CNS), where they comprise 45% of total membrane phospholipids. Plasmenyl PE is the predominant ethanolamine phospholipid in brain, with highest levels detected in white matter, and contains a vinyl ether bond in the sn-1 position that is preferentially targeted by reactive oxygen species. In this manner, plasmenyl PE acts as an important antioxidant by preventing the peroxidation of polyunsaturated fatty acids in membrane phospholipids that can trigger ferroptosis (peroxidated diacyl PE is a particularly effective executioner of ferroptosis). In humans, rare mutations in SELENOI lead to hereditary spastic paraplegia (HSP), a neurodegenerative condition affecting upper motor neurons characterized by impaired functionality of the lower limbs. The current understanding of the mechanisms governing PE/plasmenyl PE metabolism in brain is limited, in large part due to a lack of representative mouse models that allow mechanistic studies to be conducted. Our Multiple Principal Investigator (MPI)-led research team has developed a unique mouse model for mechanistic studies that will utilize our expertise in selenoprotein biochemistry and neurobiology to generate fundamental new knowledge about SELENOI function in the CNS. In particular, we have developed a unique mouse model in which SELENOI deletion is restricted to the CNS, thereby circumventing the embryonic lethality caused by constitutive SELENOI KO in mice. Our preliminary studies have revealed striking behavioral deficits that parallel those reported in humans with rare loss-of- function SELENOI mutations. This project will address the following specific aims: 1) Identify and characterize the behavioral and neuropathological alterations elicited by CNS-specific KO of SELENOI in mice; 2) Determine the cell-type specific contribution of SELENOI to phospholipid synthesis, ferroptotic vulnerability, and myelination in vitro using primary neurons and oligodendrocytes. The anticipated outcomes of these experiments are: 1) identification of the behaviors, brain regions, and cell types negatively impacted by SELENOI deficiency, 2) discernment of the influence of SELENOI upon PE/plasmenyl PE metabolism in brain, and 3) determination of whether SELENOI alters sensitivity to ferroptosis. This work will provide mechanistic insight not attainable with human samples and will lay the framework for future studies investigating the temporal and cell-type specific role of SELENOI in brain.