Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation.

Arlene C P Kiyohara,Daniel J Torres,C William R Shuttleworth,Frederick P Bellinger,Jenna Pak,Rachel H L H Rueli,Ayaka Hagiwara

doi:10.3389/fnut.2021.683154

Abstract

Selenoprotein P (SELENOP1) is a selenium-rich antioxidant protein involved in extracellular transport of selenium (Se). SELENOP1 also has metal binding properties. The trace element Zinc (Zn2+) is a neuromodulator that can be released from synaptic terminals in the brain, primarily from a subset of glutamatergic terminals. Both Zn2+ and Se are necessary for normal brain function. Although these ions can bind together with high affinity, the biological significance of an interaction of SELENOP1 with Zn2+ has not been investigated. We examined changes in brain Zn2+ in SELENOP1 knockout (KO) animals. Timm-Danscher and N-(6-methoxy-8-quinolyl)-p-toluenesulphonamide (TSQ) staining revealed increased levels of intracellular Zn2+ in the SELENOP1−/− hippocampus compared to wildtype (WT) mice. Mass spectrometry analysis of frozen whole brain samples demonstrated that total Zn2+ was not increased in the SELENOP1−/− mice, suggesting only local changes in Zn2+ distribution. Unexpectedly, live Zn2+ imaging of hippocampal slices with a selective extracellular fluorescent Zn2+ indicator (FluoZin-3) showed that SELENOP1−/− mice have impaired Zn2+ release in response to KCl-induced neuron depolarization. The zinc/metal storage protein metallothionein 3 (MT-3) was increased in SELENOP1−/− hippocampus relative to wildtype, possibly in response to an elevated Zn2+ content. We found that depriving cultured cells of selenium resulted in increased intracellular Zn2+, as did inhibition of selenoprotein GPX4 but not GPX1, suggesting the increased Zn2+ in SELENOP1−/− mice is due to a downregulation of antioxidant selenoproteins and subsequent release of Zn2+ from intracellular stores. Surprisingly, we found increased tau phosphorylation in the hippocampus of SELENOP1−/− mice, possibly resulting from intracellular zinc changes. Our findings reveal important roles for SELENOP1 in the maintenance of synaptic Zn2+ physiology and preventing tau hyperphosphorylation.

Highlights

Within the body, selenium (Se) functions primarily in the form of selenocysteine (Sec), the 21st amino acid, which is incorporated into members of the selenoprotein family [1,2,3]
A domain search of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database indicates that the human SELENOP1 protein structure has a zinc-binding domain overlapping one of the His-rich regions, which has homology to the ZIP zinc
This increase was prevented by the vitamin E compound α-tocopherol, which reduces lipid peroxidation. These findings suggest that a deficiency in Se can increase free intracellular Zn2+ by causing a reduction in GPX4, which results in increased oxidation of lipids

Summary

Introduction

Selenium (Se) functions primarily in the form of selenocysteine (Sec), the 21st amino acid, which is incorporated into members of the selenoprotein family [1,2,3]. Selenoprotein P (SELENOP1) is a selenium-rich protein with 10 Sec residues that transports Se in serum from liver to the brain and other organs [4]. SELENOP1 has been described in brain neurons [8, 9], which may be the targets of Se transport. SELENOP1 KO mice have reduced brain selenium and reduced levels of antioxidant selenoproteins such as glutathione peroxidases 1 and 4 (GPX1 and GPX4) [10]. Mice with the SELENOP1 gene deletion have deficient hippocampal synaptic function and deficits in spatial learning and long-term potentiation (LTP), a model for learning and memory [11]. SELENOP1 is increased in the brain and CSF in Alzheimer’s disease [5, 8, 12] and associated with both Alzheimer’s and Parkinson’s pathology [8, 13]

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