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000852456 1001_ $$0P:(DE-HGF)0$$aSiebzehnrübl, Florian A.$$b0$$eCorresponding author
000852456 245__ $$aEarly postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition
000852456 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2018
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000852456 520__ $$aHuntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
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000852456 7001_ $$0P:(DE-HGF)0$$aRaber, Kerstin A.$$b1
000852456 7001_ $$0P:(DE-HGF)0$$aUrbach, Yvonne K.$$b2
000852456 7001_ $$0P:(DE-HGF)0$$aSchulze-Krebs, Anja$$b3
000852456 7001_ $$0P:(DE-HGF)0$$aCanneva, Fabio$$b4
000852456 7001_ $$0P:(DE-HGF)0$$aMoceri, Sandra$$b5
000852456 7001_ $$0P:(DE-HGF)0$$aHabermeyer, Johanna$$b6
000852456 7001_ $$0P:(DE-HGF)0$$aAchoui, Dalila$$b7
000852456 7001_ $$0P:(DE-HGF)0$$aGupta, Bhavana$$b8
000852456 7001_ $$0P:(DE-HGF)0$$aSteindler, Dennis A.$$b9
000852456 7001_ $$0P:(DE-HGF)0$$aStephan, Michael$$b10
000852456 7001_ $$0P:(DE-HGF)0$$aNguyen, Huu Phuc$$b11
000852456 7001_ $$0P:(DE-HGF)0$$aBonin, Michael$$b12
000852456 7001_ $$0P:(DE-HGF)0$$aRiess, Olaf$$b13
000852456 7001_ $$0P:(DE-Juel1)131672$$aBauer, Andreas$$b14
000852456 7001_ $$0P:(DE-HGF)0$$aAigner, Ludwig$$b15
000852456 7001_ $$0P:(DE-HGF)0$$aCouillard-Despres, Sebastien$$b16
000852456 7001_ $$0P:(DE-HGF)0$$aPaucar, Martin Arce$$b17
000852456 7001_ $$0P:(DE-HGF)0$$aSvenningsson, Per$$b18
000852456 7001_ $$0P:(DE-HGF)0$$aOsmand, Alexander$$b19
000852456 7001_ $$0P:(DE-HGF)0$$aAndreew, Alexander$$b20
000852456 7001_ $$0P:(DE-HGF)0$$aZabel, Claus$$b21
000852456 7001_ $$0P:(DE-HGF)0$$aWeiss, Andreas$$b22
000852456 7001_ $$0P:(DE-HGF)0$$aKuhn, Rainer$$b23
000852456 7001_ $$0P:(DE-HGF)0$$aMoussaoui, Saliha$$b24
000852456 7001_ $$0P:(DE-HGF)0$$aBlockx, Ines$$b25
000852456 7001_ $$0P:(DE-HGF)0$$aVan der Linden, Annemie$$b26
000852456 7001_ $$0P:(DE-HGF)0$$aCheong, Rachel Y.$$b27
000852456 7001_ $$0P:(DE-HGF)0$$aRoybon, Laurent$$b28
000852456 7001_ $$0P:(DE-HGF)0$$aPetersén, Åsa$$b29
000852456 7001_ $$0P:(DE-HGF)0$$avon Hörsten, Stephan$$b30
000852456 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.1807962115$$gVol. 115, no. 37, p. E8765 - E8774$$n37$$pE8765 - E8774$$tProceedings of the National Academy of Sciences of the United States of America$$v115$$x1091-6490$$y2018
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