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(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.