The Neurobiology of Selenium: Looking Back and to the Future

Abstract

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

Keywords: GPX4; epilepsy; ferroptosis; genetics; neurodegeneration.

FIGURE 1

Conversion of iodothyronines by deiodinases and activation of the nuclear T3-receptors. The main product of the thyroid gland is thyroxine (T4, 3,3′,5,5′-tetraiodothyronine). The actions of 5′-deiodinases (DIO1 and DIO2) and 5-deiodinases (DIO1 and DIO3) lead to T3 (3,3′,5-triiodothyronine) and rT3 (3,3′,5′-triiodothyronine), respectively. Only T3 activates the nuclear T3-receptors TRα and TRβ. T2 and rT3 are thus inactive metabolites and a cell can shape its local T3 level through DIO expression. Inactivation of Dio1 as well as SECISBP2-deficiency lead to increased plasma rT3.

FIGURE 2

Biosynthetic pathway of selenoprotein translation. Transfer-RNA^Sec is charged with Ser by Seryl-tRNA synthase (Ser-RS), hence the more accurate designation tRNA^[Ser]Sec. The kinase PSTK phosphorylates Ser-tRNA^Sec. Selenophosphate synthase (SEPHS2) provides selenophosphate which is used by selenocysteine synthase (SEPSECS) to convert phosphoSer-tRNA^Sec into Sec-tRNA^Sec. EEFSEC is a translation elongation factor specific for Sec-tRNA^Sec. Canonical selenoproteins carry a selenocysteine insertion sequence (SECIS) in their mRNA in order to re-code the UGA codon as Sec codon. The dependence of UGA/Sec re-coding varies among canonical selenoproteins. Several non-canonical selenoprotein genes have been described that do not contain a SECIS element (Guo et al., 2018).