Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation.

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) is a neuromodulator that can be released from synaptic terminals in the brain, primarily from a subset of glutamatergic terminals. Both Zn 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 has not been investigated. We examined changes in brain Zn in SELENOP1 knockout (KO) animals. Timm-Danscher and N-(6-methoxy-8-quinolyl)-toluenesulphonamide (TSQ) staining revealed increased levels of intracellular Zn in the SELENOP1 hippocampus compared to wildtype (WT) mice. Mass spectrometry analysis of frozen whole brain samples demonstrated that total Zn was not increased in the SELENOP1 mice, suggesting only local changes in Zn distribution. Unexpectedly, live Zn imaging of hippocampal slices with a selective extracellular fluorescent Zn indicator (FluoZin-3) showed that SELENOP1 mice have impaired Zn 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 content. We found that depriving cultured cells of selenium resulted in increased intracellular Zn, as did inhibition of selenoprotein GPX4 but not GPX1, suggesting the increased Zn in SELENOP1 mice is due to a downregulation of antioxidant selenoproteins and subsequent release of Zn 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 physiology and preventing tau hyperphosphorylation.