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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #363661
Title: Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

Author
item SIEBZEHNRUEBL, FLORIAN - University Of Florida
item RABER, KERSTIN - Friedrich-Alexander University
item URBACH, YVONNE - Friedrich-Alexander University
item SCHULZE-KREBS, ANJA - Friedrich-Alexander University
item CANNEVA, FABIO - Friedrich-Alexander University
item MOCERI, SANDRA - Friedrich-Alexander University
item HABERMEYER, JOHANNA - Friedrich-Alexander University
item ACHOUI, DALILA - University Of Florida
item GUPTA, BHAVANA - Cardiff University
item STEINDLER, DENNIS - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item STEPHAN, MICHAEL - University Of Hannover
item NGUYEN, HUU PHUC - University Of Tubingen
item BONIN, MICHAEL - University Of Tubingen
item RIESS, OLAF - University Of Tubingen
item BAUER, ANDREAS - Forschungszentrum Juelich Gmbh
item AIGNER, LUDWIG - Paracelsus Medical Private University
item COUILLARD-DESPRES, SEBASTIEN - Paracelsus Medical Private University
item PAUCAR, MARTIN - Karolinska Institute
item SVENNINGSSON, PER - Karolinska Institute
item OSMAND, ALEXANDER - University Of Tennessee
item ANDREEW, ALEXANDER - Charite' University Hospital Berlin
item ZABEL, CLAUS - Charite' University Hospital Berlin
item WEISS, ANDREAS - Evotec
item KUHN, RAINER - Novartis
item MOUSSAOUI, SALIHA - Novartis
item BLOCKX, INES - University Of Antwerp
item VAN DER LINDEN, ANNEMIE - University Of Antwerp
item CHEONG, RACHEL - Lund University
item ROYBON, LAURENT - Lund University
item PETERSEN, ASA - Lund University
item 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.