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

Journal article


Publication Details

Author(s): Siebzehnrubl FA, Reber KA, Urbach YK, Schulze-Krebs A, Canneva F, Moceri S, Habermeyer J, Achoui D, Gupta B, Steindler DA, Stephan M, Huu Phuc Nguyen , Bonin M, Riess O, Bauer A, Aigner L, Couillard-Despres S, Paucar MA, Svenningsson P, Osmand A, Andreew A, Zabel C, Weiss A, Kuhn R, Moussaoui S, Blockx I, Van Der Linden A, Cheong RY, Roybon L, Petersen A, von Hörsten S
Journal: Proceedings of the National Academy of Sciences of the United States of America
Publication year: 2018
Volume: 115
Journal issue: 37
Pages range: E8765-E8774
ISSN: 0027-8424
eISSN: 1091-6490


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.


FAU Authors / FAU Editors

Habermeyer, Johanna
Professur für Experimentelle Biomedizin
Moceri, Sandra
Professur für Experimentelle Biomedizin
von Hörsten, Stephan Prof. Dr.
Professur für Experimentelle Biomedizin


External institutions with authors

Cardiff University
Charité - Universitätsmedizin Berlin
Eberhard Karls Universität Tübingen
Forschungszentrum Jülich / Research Centre Jülich (FZJ)
Karolinska Institute
Lund University / Lunds universitet
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Novartis AG
Paracelsus Medizinische Privatuniversität
University of Antwerp / Universiteit Antwerpen
University of Florida
University of Tennessee (UTK)


How to cite

APA:
Siebzehnrubl, F.A., Reber, K.A., Urbach, Y.K., Schulze-Krebs, A., Canneva, F., Moceri, S.,... von Hörsten, S. (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 of the United States of America, 115(37), E8765-E8774. https://dx.doi.org/10.1073/pnas.1807962115

MLA:
Siebzehnrubl, Florian A., et al. "Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition." Proceedings of the National Academy of Sciences of the United States of America 115.37 (2018): E8765-E8774.

BibTeX: 

Last updated on 2019-06-08 at 09:08