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

Siebzehnrübl, Florian A. (author)
University of Florida,Cardiff University,Charité - University Medicine Berlin
Raber, Kerstin A. (author)
Friedrich-Alexander University Erlangen-Nürnberg,Jülich Research Centre
Urbach, Yvonne K. (author)
Friedrich-Alexander University Erlangen-Nürnberg
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Schulze-Krebs, Anja (author)
Friedrich-Alexander University Erlangen-Nürnberg
Canneva, Fabio (author)
Friedrich-Alexander University Erlangen-Nürnberg
Moceri, Sandra (author)
Friedrich-Alexander University Erlangen-Nürnberg
Habermeyer, Johanna (author)
Friedrich-Alexander University Erlangen-Nürnberg
Achoui, Dalila (author)
University of Florida
Gupta, Bhavana (author)
Cardiff University
Steindler, Dennis A. (author)
University of Florida,Tufts University
Stephan, Michael (author)
Hannover Medical School
Nguyen, Huu Phuc (author)
University of Tübingen
Bonin, Michael (author)
University of Tübingen
Riess, Olaf (author)
University of Tübingen
Bauer, Andreas (author)
Jülich Research Centre
Aigner, Ludwig (author)
Paracelsus Private Medical University of Salzburg
Couillard-Despres, Sebastien (author)
Paracelsus Private Medical University of Salzburg
Paucar, Martin Arce (author)
Karolinska Institute
Svenningsson, Per (author)
Karolinska Institutet,Karolinska Institute
Osmand, Alexander (author)
University of Tennessee
Andreew, Alexander (author)
Charité - University Medicine Berlin
Zabel, Claus (author)
Charité - University Medicine Berlin
Weiss, Andreas (author)
Novartis Pharma AG
Kuhn, Rainer (author)
Novartis Pharma AG
Moussaoui, Saliha (author)
Novartis Pharma AG
Blockx, Ines (author)
University of Antwerp
Van der Linden, Annemie (author)
University of Antwerp
Cheong, Rachel Y. (author)
Lund University,Lunds universitet,Translationell neuroendokrinologi,Forskargrupper vid Lunds universitet,Translational Neuroendocrinology,Lund University Research Groups
Roybon, Laurent (author)
Lund University,Lunds universitet,Stamcellslaboratoriet för sjukdomsmodellering i det centrala nervsystemet,Forskargrupper vid Lunds universitet,IPSC Laboratory for CNS Disease Modeling,Lund University Research Groups
Petersén, Åsa (author)
Lund University,Lunds universitet,Translationell neuroendokrinologi,Forskargrupper vid Lunds universitet,Translational Neuroendocrinology,Lund University Research Groups
Von Hörsten, Stephan (author)
Friedrich-Alexander University Erlangen-Nürnberg
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 (creator_code:org_t)
2018-08-27
2018
English.
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:37, s. 8765-8774
Related links:
http://dx.doi.org/10...
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https://www.pnas.org...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Keyword

Animal model
Development
Experimental therapy
Multiomics
Neurodegeneration

Publication and Content Type

art (subject category)
ref (subject category)

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