ArrayExpress Uploader06900wild type genotypewild type genotypewild type genotypewild type genotypewild type genotypewild type genotypewild type genotypewild type genotypeR6/2::HDAC4hetR6/2::HDAC4hetR6/2::HDAC4hetR6/2::HDAC4hetR6/2::HDAC4hetR6/2::HDAC4hetR6/2::HDAC4hetR6/2::HDAC4hetR6/2R6/2R6/2R6/2R6/2R6/2R6/2R6/2R6/2HDAC4hetHDAC4hetHDAC4hetHDAC4hetHDAC4hetHDAC4hetHDAC4hetHDAC4hetHDAC4hetarrayexpress_sid6[u"Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be...24302884E-GEOD-38219/profile/8773/arrayexpressuploader134diseaseglutaminehistonehuntington's diseaseproteinDec.12, 2014Falsegene-expression-data-from-cortex-of-15-week-old-wiE-GEOD-38219_A-AFFY-45Gene expression data from cortex of 15 week old wild type, R6/2, HDAC4het and R6/2::HDAC4het miceNov.12, 2014[u"Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics. mRNA expression analysis was performed by microarray in 15 weeks old WT (n=8), R6/2 (n=9), HDAC4het (n=8) and Double R6/2::HDAC4het (n=9) mice. Microarray quality control was performed using the software package provided on RACE (", {u'a': {u'href': u'http://race.unil.ch', u'target': u'_blank', u'$': u'http://race.unil.ch'}}, u').']http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-38219mousehttp://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-38219/samples/