Author
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SIEBZEHNRUEBL, FLORIAN - University Of Florida |
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RABER, KERSTIN - Friedrich-Alexander University |
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URBACH, YVONNE - Friedrich-Alexander University |
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SCHULZE-KREBS, ANJA - Friedrich-Alexander University |
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CANNEVA, FABIO - Friedrich-Alexander University |
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MOCERI, SANDRA - Friedrich-Alexander University |
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HABERMEYER, JOHANNA - Friedrich-Alexander University |
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ACHOUI, DALILA - University Of Florida |
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GUPTA, BHAVANA - Cardiff University |
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STEINDLER, DENNIS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University |
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STEPHAN, MICHAEL - University Of Hannover |
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NGUYEN, HUU PHUC - University Of Tubingen |
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BONIN, MICHAEL - University Of Tubingen |
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RIESS, OLAF - University Of Tubingen |
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BAUER, ANDREAS - Forschungszentrum Juelich Gmbh |
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AIGNER, LUDWIG - Paracelsus Medical Private University |
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COUILLARD-DESPRES, SEBASTIEN - Paracelsus Medical Private University |
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PAUCAR, MARTIN - Karolinska Institute |
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SVENNINGSSON, PER - Karolinska Institute |
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OSMAND, ALEXANDER - University Of Tennessee |
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ANDREEW, ALEXANDER - Charite' University Hospital Berlin |
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ZABEL, CLAUS - Charite' University Hospital Berlin |
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WEISS, ANDREAS - Evotec |
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KUHN, RAINER - Novartis |
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MOUSSAOUI, SALIHA - Novartis |
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BLOCKX, INES - University Of Antwerp |
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VAN DER LINDEN, ANNEMIE - University Of Antwerp |
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CHEONG, RACHEL - Lund University |
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ROYBON, LAURENT - Lund University |
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PETERSEN, ASA - Lund University |
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VAN HOERSTEN, STEPHAN - Friedrich-Alexander University |
Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 7/26/2018 Publication Date: 8/27/2018 Citation: Siebzehnruebl, F.A., Raber, K.A., Urbach, Y.K., Schulze-Krebs, A., Canneva, F., Moceri, S., Habermeyer, J., Achoui, D., Gupta, B., Steindler, D.A., Stephan, M., Nguyen, H., Bonin, M., Riess, O., Bauer, A., Aigner, L., Couillard-Despres, S., Paucar, M.A., Svenningsson, P., Osmand, A., Andreew, A., Zabel, C., Weiss, A., Kuhn, R., Moussaoui, S., Blockx, I., Van Der Linden, A., Cheong, R.Y., Roybon, L., Petersen, A., Van Hoersten, 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. 115(37):E8765-E8774. https://doi.org/10.1073/pnas.1807962115. DOI: https://doi.org/10.1073/pnas.1807962115 Interpretive Summary: The mutant gene that causes Huntington's disease (HD) leads to a brain degenerative disorder. Even though the mutant gene is expressed during embryonic development, HD usually manifests in adulthood following a long pre-disease, or prodromal period where altered movements, behaviors or other hallmarks of disease are not obvious. The present study used transgenic rodent models of HD to test whether altering DNA, using what is called an inhibitor of histone deacetylase that affects global gene function, might potentially slow or even halt disease processes earlier by identifying early postnatal behavioral, molecular and cellular changes in transgenic HD animals. We found that reduced ultrasonic vocalizations, certain changes in the physiology of brain circuits, and increased risk taking are accompanied by disturbances in the regulation of the neurotransmitter dopamine involved in movement and other functions, as well as altered neural stem cell function. Use of a pharmaceutical inhibitor of histone deacetylase led to significant improvement of behavioral changes and markers of dopaminergic neurotransmission as well as a complete reversal of abnormal brain cell generation in different rodent models of HD. Technical Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Though mutant HTT is expressed during embryonic development, clinical HD usually manifests in adulthood. Here, we identify early postnatal behavioral, molecular and cellular changes in transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of pre-pulse inhibition and increased risk taking are accompanied by disturbances of dopaminergic regulation, as well as reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells. Treatment of this early phenotype with a histone deacetylase inhibitor (HDACi, LBH589) led to significant improvement of behavioral changes and markers of dopaminergic neurotransmission as well as a complete reversal of aberrant neuronal differentiation. Our data suggest that HD might be considered a neurodevelopmental disorder and that pre-symptomatic intervention using HDACi may represent a promising novel treatment approach for HD. |