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 (Zn2+) is a neuromodulator that can be released from synaptic terminals in the brain, primarily from a subset of...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-07-01
|
| Series: | Frontiers in Nutrition |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnut.2021.683154/full |
| _version_ | 1818576170071883776 |
|---|---|
| author | Arlene C. P. Kiyohara Daniel J. Torres Daniel J. Torres Ayaka Hagiwara Jenna Pak Rachel H. L. H. Rueli C. William R. Shuttleworth Frederick P. Bellinger |
| author_facet | Arlene C. P. Kiyohara Daniel J. Torres Daniel J. Torres Ayaka Hagiwara Jenna Pak Rachel H. L. H. Rueli C. William R. Shuttleworth Frederick P. Bellinger |
| author_sort | Arlene C. P. Kiyohara |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T06:09:45Z |
| format | Article |
| id | doaj.art-224a84d737694c99bdf7da6b4e38813e |
| institution | Directory Open Access Journal |
| issn | 2296-861X |
| language | English |
| last_indexed | 2024-12-16T06:09:45Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Nutrition |
| spelling | doaj.art-224a84d737694c99bdf7da6b4e38813e2022-12-21T22:41:25ZengFrontiers Media S.A.Frontiers in Nutrition2296-861X2021-07-01810.3389/fnut.2021.683154683154Selenoprotein P Regulates Synaptic Zinc and Reduces Tau PhosphorylationArlene C. P. Kiyohara0Daniel J. Torres1Daniel J. Torres2Ayaka Hagiwara3Jenna Pak4Rachel H. L. H. Rueli5C. William R. Shuttleworth6Frederick P. Bellinger7Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, United StatesDepartment of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, United StatesPacific Biosciences Research Center, School of Ocean and Earth Science and Technology, University of Hawaii at Manoa, Honolulu, HI, United StatesDepartment of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, United StatesDepartment of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, United StatesDepartment of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, United StatesDepartment of Neurosciences, University of New Mexico, Albuquerque, NM, United StatesDepartment of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, United StatesSelenoprotein 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.https://www.frontiersin.org/articles/10.3389/fnut.2021.683154/fullSelenoprotein PzincAlzheimer's diseasetauselenium |
| spellingShingle | Arlene C. P. Kiyohara Daniel J. Torres Daniel J. Torres Ayaka Hagiwara Jenna Pak Rachel H. L. H. Rueli C. William R. Shuttleworth Frederick P. Bellinger Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation Frontiers in Nutrition Selenoprotein P zinc Alzheimer's disease tau selenium |
| title | Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation |
| title_full | Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation |
| title_fullStr | Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation |
| title_full_unstemmed | Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation |
| title_short | Selenoprotein P Regulates Synaptic Zinc and Reduces Tau Phosphorylation |
| title_sort | selenoprotein p regulates synaptic zinc and reduces tau phosphorylation |
| topic | Selenoprotein P zinc Alzheimer's disease tau selenium |
| url | https://www.frontiersin.org/articles/10.3389/fnut.2021.683154/full |
| work_keys_str_mv | AT arlenecpkiyohara selenoproteinpregulatessynapticzincandreducestauphosphorylation AT danieljtorres selenoproteinpregulatessynapticzincandreducestauphosphorylation AT danieljtorres selenoproteinpregulatessynapticzincandreducestauphosphorylation AT ayakahagiwara selenoproteinpregulatessynapticzincandreducestauphosphorylation AT jennapak selenoproteinpregulatessynapticzincandreducestauphosphorylation AT rachelhlhrueli selenoproteinpregulatessynapticzincandreducestauphosphorylation AT cwilliamrshuttleworth selenoproteinpregulatessynapticzincandreducestauphosphorylation AT frederickpbellinger selenoproteinpregulatessynapticzincandreducestauphosphorylation |