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

Fernando J. Bustos, Estibaliz Ampuero, Nur Jury, Rodrigo Aguilar, Fahimeh Falahi, Jorge Toledo, Juan Ahumada, Jaclyn Lata, Paula Cubillos, Berta Henríquez, Miguel V. Guerra, Jimmy Stehberg, Rachael L. Neve, Nibaldo C. Inestrosa, Ursula Wyneken, Marco Fuenzalida, Steffen Härtel, Miguel Sena-Esteves, Lorena Varela-Nallar, Marianne G. Rots & 2 otros Martin Montecino, Brigitte Van Zundert

Resultado de la investigación: Article

19 Citas (Scopus)

Resumen

The 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.

Idioma originalEnglish
Páginas (desde-hasta)3252-3268
Número de páginas17
PublicaciónBrain
Volumen140
N.º12
DOI
EstadoPublished - 1 dic 2017

Huella dactilar

Post-Synaptic Density
Epigenomics
Cognition
Alzheimer Disease
Proteins
Transcription Factors
Histone Code
Gene Targeting
Huntington Disease
Zinc Fingers
Memory Disorders
Glutamate Receptors
Nervous System Diseases
Neurodegenerative Diseases
Genes

ASJC Scopus subject areas

  • Clinical Neurology

Citar esto

Bustos, Fernando J. ; Ampuero, Estibaliz ; Jury, Nur ; Aguilar, Rodrigo ; Falahi, Fahimeh ; Toledo, Jorge ; Ahumada, Juan ; Lata, Jaclyn ; Cubillos, Paula ; Henríquez, Berta ; Guerra, Miguel V. ; Stehberg, Jimmy ; Neve, Rachael L. ; Inestrosa, Nibaldo C. ; Wyneken, Ursula ; Fuenzalida, Marco ; Härtel, Steffen ; Sena-Esteves, Miguel ; Varela-Nallar, Lorena ; Rots, Marianne G. ; Montecino, Martin ; Van Zundert, Brigitte. / Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice. En: Brain. 2017 ; Vol. 140, N.º 12. pp. 3252-3268.
@article{2144db61ea254e68bfee7d8ed4dac374,
title = "Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice",
abstract = "The 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.",
keywords = "Alzheimer's disease, ATF, epigenetics, PSD-95, ZFP",
author = "Bustos, {Fernando J.} and Estibaliz Ampuero and Nur Jury and Rodrigo Aguilar and Fahimeh Falahi and Jorge Toledo and Juan Ahumada and Jaclyn Lata and Paula Cubillos and Berta Henr{\'i}quez and Guerra, {Miguel V.} and Jimmy Stehberg and Neve, {Rachael L.} and Inestrosa, {Nibaldo C.} and Ursula Wyneken and Marco Fuenzalida and Steffen H{\"a}rtel and Miguel Sena-Esteves and Lorena Varela-Nallar and Rots, {Marianne G.} and Martin Montecino and {Van Zundert}, Brigitte",
year = "2017",
month = "12",
day = "1",
doi = "10.1093/brain/awx272",
language = "English",
volume = "140",
pages = "3252--3268",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "12",

}

Bustos, FJ, Ampuero, E, Jury, N, Aguilar, R, Falahi, F, Toledo, J, Ahumada, J, Lata, J, Cubillos, P, Henríquez, B, Guerra, MV, Stehberg, J, Neve, RL, Inestrosa, NC, Wyneken, U, Fuenzalida, M, Härtel, S, Sena-Esteves, M, Varela-Nallar, L, Rots, MG, Montecino, M & Van Zundert, B 2017, 'Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice', Brain, vol. 140, n.º 12, pp. 3252-3268. https://doi.org/10.1093/brain/awx272

Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice. / Bustos, Fernando J.; Ampuero, Estibaliz; Jury, Nur; Aguilar, Rodrigo; Falahi, Fahimeh; Toledo, Jorge; Ahumada, Juan; Lata, Jaclyn; Cubillos, Paula; Henríquez, Berta; Guerra, Miguel V.; Stehberg, Jimmy; Neve, Rachael L.; Inestrosa, Nibaldo C.; Wyneken, Ursula; Fuenzalida, Marco; Härtel, Steffen; Sena-Esteves, Miguel; Varela-Nallar, Lorena; Rots, Marianne G.; Montecino, Martin; Van Zundert, Brigitte.

En: Brain, Vol. 140, N.º 12, 01.12.2017, p. 3252-3268.

Resultado de la investigación: Article

TY - JOUR

T1 - Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice

AU - Bustos, Fernando J.

AU - Ampuero, Estibaliz

AU - Jury, Nur

AU - Aguilar, Rodrigo

AU - Falahi, Fahimeh

AU - Toledo, Jorge

AU - Ahumada, Juan

AU - Lata, Jaclyn

AU - Cubillos, Paula

AU - Henríquez, Berta

AU - Guerra, Miguel V.

AU - Stehberg, Jimmy

AU - Neve, Rachael L.

AU - Inestrosa, Nibaldo C.

AU - Wyneken, Ursula

AU - Fuenzalida, Marco

AU - Härtel, Steffen

AU - Sena-Esteves, Miguel

AU - Varela-Nallar, Lorena

AU - Rots, Marianne G.

AU - Montecino, Martin

AU - Van Zundert, Brigitte

PY - 2017/12/1

Y1 - 2017/12/1

N2 - The 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.

AB - The 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.

KW - Alzheimer's disease

KW - ATF

KW - epigenetics

KW - PSD-95

KW - ZFP

UR - http://www.scopus.com/inward/record.url?scp=85038232228&partnerID=8YFLogxK

U2 - 10.1093/brain/awx272

DO - 10.1093/brain/awx272

M3 - Article

VL - 140

SP - 3252

EP - 3268

JO - Brain

JF - Brain

SN - 0006-8950

IS - 12

ER -