Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

Research output: Contribution to journalArticle

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.

Details

Authors
  • Florian A. Siebzehnrübl
  • Kerstin A. Raber
  • Yvonne K. Urbach
  • Anja Schulze-Krebs
  • Fabio Canneva
  • Sandra Moceri
  • Johanna Habermeyer
  • Dalila Achoui
  • Bhavana Gupta
  • Dennis A. Steindler
  • Michael Stephan
  • Huu Phuc Nguyen
  • Michael Bonin
  • Olaf Riess
  • Andreas Bauer
  • Ludwig Aigner
  • Sebastien Couillard-Despres
  • Martin Arce Paucar
  • Per Svenningsson
  • Alexander Osmand
  • Alexander Andreew
  • Claus Zabel
  • Andreas Weiss
  • Rainer Kuhn
  • Saliha Moussaoui
  • Ines Blockx
  • Annemie Van der Linden
  • Stephan Von Hörsten
Organisations
External organisations
  • Cardiff University
  • Friedrich-Alexander University Erlangen-Nürnberg
  • Tufts University
  • Hannover Medical School
  • University of Tübingen
  • Jülich Research Centre
  • Paracelsus Private Medical University of Salzburg
  • Karolinska Institutet
  • University of Tennessee
  • Charité Universitätsmedizin Berlin
  • Novartis Pharma AG
  • University of Antwerp
  • University of Florida
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences

Keywords

  • Animal model, Development, Experimental therapy, Multiomics, Neurodegeneration
Original languageEnglish
Pages (from-to)E8765-E8774
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number37
Publication statusPublished - 2018 Sep 11
Publication categoryResearch
Peer-reviewedYes