Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation
Arlene C. P. Kiyohara, Daniel J. Torres, Ayaka Hagiwara, Jenna Pak, Rachel H. Rueli, C. William Shuttleworth, Frederick P. Bellinger
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 (Zn 2+ ) is a neuromodulator that can be released from synaptic terminals in the brain, primarily from a subset of glutamatergic terminals. Both Zn 2+ 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 Zn 2+ has not been investigated. We examined changes in brain Zn 2+ in SELENOP1 knockout (KO) animals. Timm-Danscher and N-(6-methoxy-8-quinolyl)- p- toluenesulphonamide (TSQ) staining revealed increased levels of intracellular Zn 2+ in the SELENOP1 −/− hippocampus compared to wildtype (WT) mice. Mass spectrometry analysis of frozen whole brain samples demonstrated that total Zn 2+ was not increased in the SELENOP1 −/− mice, suggesting only local changes in Zn 2+ distribution. Unexpectedly, live Zn 2+ imaging of hippocampal slices with a selective extracellular fluorescent Zn 2+ indicator (FluoZin-3) showed that SELENOP1 −/− mice have impaired Zn 2+ 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 Zn 2+ content. We found that depriving cultured cells of selenium resulted in increased intracellular Zn 2+ , as did inhibition of selenoprotein GPX4 but not GPX1, suggesting the increased Zn 2+ in SELENOP1 −/− mice is due to a downregulation of antioxidant selenoproteins and subsequent release of Zn 2+ 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 Zn 2+ physiology and preventing tau hyperphosphorylation.