Selenoproteins in nervous system development and function

Abstract

Selenoproteins are a distinct class of proteins that are characterized by the co-translational incorporation of selenium (Se) in the form of the 21st amino acid selenocysteine. Selenoproteins provide a key defense against oxidative stress, as many of these proteins participate in oxidation-reduction reactions neutralizing reactive oxygen species, where selenocysteine residues act as catalytic sites. Many selenoproteins are highly expressed in the brain, and mouse knockout studies have determined that several are required for normal brain development. In parallel with these laboratory studies, recent reports of rare human cases with mutations in genes involved in selenoprotein biosynthesis have described individuals with an assortment of neurological problems that mirror those detailed in knockout mice. These deficits include impairments in cognition and motor function, seizures, hearing loss, and altered thyroid metabolism. Additionally, due to the fact that oxidative stress is a key feature of neurodegenerative disease, there is considerable interest in the therapeutic potential of selenium supplementation for human neurological disorders. Studies performed in cell culture and rodent models have demonstrated that selenium administration attenuates oxidative stress, prevents neurodegeneration, and counters cell signaling mechanisms known to be dysregulated in certain disease states. However, there is currently no definitive evidence in support of selenium supplementation to prevent and/or treat common neurological conditions in the general population. It appears likely that, in humans, supplementation with selenium may only benefit certain subpopulations, such as those that are either selenium-deficient or possess genetic variants that affect selenium metabolism.

Figure 1. Overview of selenocysteine biosynthesis and degradation

tRNA^[Ser]Sec is aminoacylated with serine by Ser-tRNA synthase, followed by serine phosphorylation by phosphoseryl-tRNA kinase to yield phosphoseryl-tRNA^[Ser]Sec. The tRNA-bound phosphoseryl residue is then converted to Sec by the enzyme selenocysteine synthase (Sec synthase), a reaction in which Se, in the form of monoselenophosphate, is transferred to tRNA^[Ser]Sec to produce Sec-tRNA^[Ser]Sec. During selenoprotein synthesis, Sec-tRNA^[Ser]Sec insertion occurs at UGA codons when directed by SECIS elements within selenoprotein mRNAs. Upon degradation, selenocysteine lyase decomposes Sec into L-alanine and selenide (represented as HSe⁻), enabling Se to be recycled for additional Sec biosynthesis.

Figure 2. Model of SelP-mediated selenium distribution in the brain

Within the brain, SelP is synthesized and secreted primarily by astrocytes. ApoER2 mediates SelP uptake into neurons and the Se present is utilized in selenoprotein synthesis. Selenoproteins support normal cell function by neutralizing reactive oxygen species (ROS). PV-interneurons represent a class of metabolically active neurons in which ApoER2 is highly expressed. These neurons have been reported to be particularly affected in several mouse models of impaired selenium metabolism in the brain. It also important to note that SelP is not the sole source of Se for neuronal selenoprotein synthesis, as increasing dietary Se intake largely prevents neurological dysfunction and normalizes brain selenoprotein levels in SelP^−/− mice.