Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Siebzehnrubl, Florian A., Raber, Kerstin A., Urbach, Yvonne K., Schulze-Krebs, Anja, Canneva, Fabio, Moceri, Sandra, Habermeyer, Johanna, Achoui, Dalila, Gupta, Bhavana, Steindler, Dennis A., Stephan, Michael, Nguyen, Huu Phuc, Bonin, Michael, Riess, Olaf, Bauer, Andreas, Aigner, Ludwig, Couillard-Despres, Sebastien, Paucar, Martin Arce, Svenningsson, Per, Osmand, Alexander, Andreew, Alexander, Zabel, Claus, Weiss, Andreas, Kuhn, Rainer, Moussaoui, Saliha, Blockx, Ines, Van der Linden, Annemie, Cheong, Rachel Y., Roybon, Laurent, Petersén, Åsa and von Hörsten, Stephan 2018. Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition. Proceedings of the National Academy of Sciences 115 (37) , E8765-E8774. 10.1073/pnas.1807962115

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (3MB) | Preview

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of First Compliant Deposit: 3 September 2018
Date of Acceptance: 26 July 2018
Last Modified: 10 Oct 2018 13:54
URI: http://orca.cf.ac.uk/id/eprint/114551

Citation Data

Cited 3 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics