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

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 (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 115

Pages Range: E8765-E8774

Journal Issue: 37

DOI: 10.1073/pnas.1807962115

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.

Authors with CRIS profile

Sandra Moceri Professur für Experimentelle Biomedizin Johanna Habermeyer Professur für Experimentelle Biomedizin Stephan von Hörsten Professur für Experimentelle Biomedizin

Involved external institutions

University of Florida US United States (USA) (US) Cardiff University GB United Kingdom (GB) Novartis AG CH Switzerland (CH) University of Antwerp / Universiteit Antwerpen BE Belgium (BE) Karolinska Institute SE Sweden (SE) Lund University / Lunds universitet SE Sweden (SE) University of Tennessee (UTK) US United States (USA) (US) Charité - Universitätsmedizin Berlin DE Germany (DE) Forschungszentrum Jülich / Research Centre Jülich (FZJ) DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Paracelsus Medizinische Privatuniversität AT Austria (AT) Eberhard Karls Universität Tübingen DE Germany (DE)

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://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.

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