Journal Article

FZJ-2018-05402

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

Siebzehnrübl, F. A. (Corresponding author) ; 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. P. ; Bonin, M. ; Riess, O. ; Bauer, A.FZJ* ; 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. ; Petersén, Å. ; von Hörsten, S.

2018
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/19792  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.

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Contributing Institute(s):

1. Molekulare Organisation des Gehirns (INM-2)

Research Program(s):

1. 573 - Neuroimaging (POF3-573) (POF3-573)

Appears in the scientific report 2018

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Database coverage:
; ; ; BIOSIS Previews ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; National-Konsortium ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection ; Zoological Record

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