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 Henriquez, Miguel V. Guerra, Jimmy Stehberg, Rachael L. Neve, Nibaldo C. Inestrosa, Ursula Wyneken, Marco Fuenzalida, Steffen Hartel, Miguel Sena-Esteves, Lorena Varela-Nallar, Marianne G. RotsMartin Montecino, Brigitte van Zundert

Research output: Contribution to journalArticleAcademicpeer-review

83 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3252-3268
Number of pages17
JournalBrain
Volume140
DOIs
Publication statusPublished - 1-Dec-2017

Keywords

  • ATF
  • ZFP
  • PSD-95
  • epigenetics
  • Alzheimer's disease
  • ARTIFICIAL TRANSCRIPTION FACTORS
  • MOUSE MODEL
  • IN-VIVO
  • DNA METHYLATION
  • NMDA RECEPTORS
  • HISTONE MODIFICATIONS
  • HIPPOCAMPAL-NEURONS
  • MUSCULAR-DYSTROPHY
  • EXPRESSION

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