{"doi":"10.3389/fnut.2021.683154","title":"Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation","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.","journal":"Frontiers in Nutrition","year":2021,"id":174620,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":302887,"name":"Daniel J. Torres","orcid":"0000-0002-4451-712X","position":1,"is_corresponding":false},{"id":714766,"name":"Ayaka Hagiwara","orcid":null,"position":2,"is_corresponding":false},{"id":714767,"name":"Jenna Pak","orcid":null,"position":3,"is_corresponding":false},{"id":714768,"name":"Rachel H. Rueli","orcid":null,"position":4,"is_corresponding":false},{"id":303923,"name":"C. William Shuttleworth","orcid":"0000-0002-0237-4888","position":5,"is_corresponding":false},{"id":714769,"name":"Frederick P. Bellinger","orcid":null,"position":6,"is_corresponding":false},{"id":714765,"name":"Arlene C. P. Kiyohara","orcid":null,"position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:47:06.584146Z","pmid":"34277682","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}