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

Siebzehnrübl, Florian A.; Raber, Kerstin A.; Urbach, Yvonne K.; Schulze-Krebs, Anja; Canneva, Fabio; Moceri, Sandra; Habermeyer, Johanna; Achoui, Dalila; Gupta, Bhavana and Steindler, Dennis A., et al. (2018) In Proceedings of the National Academy of Sciences of the United States of America 115(37). p.8765-8774
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... (More)

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.

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keywords
Animal model, Development, Experimental therapy, Multiomics, Neurodegeneration
in
Proceedings of the National Academy of Sciences of the United States of America
volume
115
issue
37
pages
8765 - 8774
publisher
National Acad Sciences
external identifiers
  • scopus:85053050954
ISSN
0027-8424
DOI
10.1073/pnas.1807962115
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English
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yes
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eaa7d714-14f9-42c1-b170-7b508884ec13
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2018-10-11 12:13:30
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2019-04-23 04:40:20
@article{eaa7d714-14f9-42c1-b170-7b508884ec13,
  abstract     = {<p>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.</p>},
  author       = {Siebzehnrübl, Florian A. and Raber, Kerstin A. and Urbach, Yvonne K. and Schulze-Krebs, Anja and Canneva, Fabio and Moceri, Sandra and Habermeyer, Johanna and Achoui, Dalila and Gupta, Bhavana and Steindler, Dennis A. and Stephan, Michael and Nguyen, Huu Phuc and Bonin, Michael and Riess, Olaf and Bauer, Andreas and Aigner, Ludwig and Couillard-Despres, Sebastien and Paucar, Martin Arce and Svenningsson, Per and Osmand, Alexander and Andreew, Alexander and Zabel, Claus and Weiss, Andreas and Kuhn, Rainer and Moussaoui, Saliha and Blockx, Ines and Van der Linden, Annemie and Cheong, Rachel Y. and Roybon, Laurent and Petersén, Åsa and Von Hörsten, Stephan},
  issn         = {0027-8424},
  keyword      = {Animal model,Development,Experimental therapy,Multiomics,Neurodegeneration},
  language     = {eng},
  month        = {09},
  number       = {37},
  pages        = {8765--8774},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition},
  url          = {http://dx.doi.org/10.1073/pnas.1807962115},
  volume       = {115},
  year         = {2018},
}