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Zinc binding to S100B affords regulation of trace metal homeostasis and excitotoxicity in the brain

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dc.contributor.author Hagmeyer, Simone
dc.contributor.author Cristóvão, Joana S.
dc.contributor.author Mulvihill, John J.E.
dc.contributor.author Boeckers, Tobias M.
dc.contributor.author Gomes, Cláudio M.
dc.contributor.author Grabrucker, Andreas M.
dc.date.accessioned 2018-01-19T09:46:45Z
dc.date.available 2018-01-19T09:46:45Z
dc.date.issued 2018
dc.identifier.uri http://hdl.handle.net/10344/6464
dc.description peer-reviewed en_US
dc.description.abstract Neuronal metal ions such as zinc are essential for brain function. In particular synaptic processes are tightly related to metal and protein homeostasis, for example through extracellular metal-binding proteins. One such protein is neuronal S100B, a calcium and zinc binding damage-associated molecular pattern (DAMP), whose chronic upregulation is associated with aging, Alzheimer’s disease (AD), motor neuron disease and traumatic brain injury (TBI). Despite gained insights on the structure of S100B, it remains unclear how its calcium and zinc binding properties regulate its function on cellular level. Here we report a novel role of S100B in trace metal homeostasis, in particular the regulation of zinc levels in the brain. Our results show that S100B at increased extracellular levels is not toxic, persists at high levels, and is taken up into neurons, as shown by cell culture and biochemical analysis. Combining protein bioimaging and zinc quantitation, along with a zinc-binding impaired S100B variant, we conclude that S100B effectively scavenges zinc ions through specific binding, resulting in a redistribution of the intracellular zinc pool. Our results indicate that scavenging of zinc by increased levels of S100B affects calcium levels in vitro. Thereby S100B is able to mediate the cross talk between calcium and zinc homeostasis. Further, we investigated a possible new neuroprotective role of S100B in excitotoxicity via its effects on calcium and zinc homeostasis. Exposure of cells to zinc-S100B but not the zinc-binding impaired S100B results in an inhibition of excitotoxicity. We conclude that in addition to its known functions, S100B acts as sensor and regulator of elevated zinc levels in the brain and this metal-buffering activity is tied to a neuroprotective role. en_US
dc.language.iso eng en_US
dc.publisher Frontiers Media en_US
dc.relation.ispartofseries Frontiers in Molecular Neuroscience;10, article , 456
dc.rights This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission. en_US
dc.subject Zn en_US
dc.subject zinc en_US
dc.subject S100B en_US
dc.subject DAMP en_US
dc.subject synapse en_US
dc.subject calcium en_US
dc.subject excitotoxicity en_US
dc.subject zinc sensor en_US
dc.title Zinc binding to S100B affords regulation of trace metal homeostasis and excitotoxicity in the brain en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US
dc.identifier.doi 10.3389/fnmol.2017.00456
dc.contributor.sponsor Evangelisches Studienwerk Villigst e.V. en_US
dc.contributor.sponsor Else-Kröner-Fresenius Stiftung en_US
dc.relation.projectid PT/FB/BL-2014-343 en_US
dc.relation.projectid UID/MULTI/04046/2013 en_US
dc.relation.projectid PTDC/NEUNMC/2138/2014 en_US
dc.relation.projectid IF/01046/2014 en_US
dc.relation.projectid SFRH/BD/101171/2014 en_US
dc.rights.accessrights info:eu-repo/semantics/openAccess en_US
dc.internal.rssid 2736674
dc.internal.rssid 2737897


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