Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice

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dc.contributor.authorBustos, Fernando J.
dc.contributor.authorAmpuero, Estibaliz
dc.contributor.authorJury, Nur
dc.contributor.authorAguilar, Rodrigo
dc.contributor.authorFalahi, Fahimeh
dc.contributor.authorToledo, Jorge
dc.contributor.authorAhumada, Juan
dc.contributor.authorLata, Jaclyn
dc.contributor.authorCubillos, Paula
dc.contributor.authorHenríquez, Berta
dc.contributor.authorGuerra, Miguel V.
dc.contributor.authorStehberg, Jimmy
dc.contributor.authorNeve, Rachael L.
dc.contributor.authorInestrosa, Nibaldo C.
dc.contributor.authorWyneken, Ursula
dc.contributor.authorFuenzalida, Marco
dc.contributor.authorHärtel, Steffen
dc.contributor.authorSena-Esteves, Miguel
dc.contributor.authorVarela-Nallar, Lorena
dc.contributor.authorRots, Marianne G.
dc.contributor.authorMontecino, Martin
dc.contributor.authorVan Zundert, Brigitte
dc.date.accessioned2023-09-27T18:00:48Z
dc.date.available2023-09-27T18:00:48Z
dc.date.issued2017-12
dc.descriptionIndexación: Scopuses
dc.description.abstractThe Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer's disease and Huntington's disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer's disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders. © 2017 The Author. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.es
dc.description.urihttps://academic-oup-com.recursosbiblioteca.unab.cl/brain/article/140/12/3252/4632922
dc.identifier.citationBrain Volume 140, Issue 12, Pages 3252 - 32681 December 2017es
dc.identifier.doi10.1093/brain/awx272
dc.identifier.issn0006-8950
dc.identifier.urihttps://repositorio.unab.cl/xmlui/handle/ria/53355
dc.language.isoenes
dc.publisherBRAIAes
dc.rights.licenseAtribución 4.0 Internacional (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.es
dc.subjectAlzheimer's diseasees
dc.subjectATFes
dc.subjectepigeneticses
dc.subjectPSD-95es
dc.subjectZFPes
dc.titleEpigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease micees
dc.typeArtículoes
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