Gene expression data from cortex of 9w old WT, R6/2, HDAC4het and R6/2::HDAC4het mice

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 Huntingtons 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.

37

Mielcarek M, Landles C, Weiss A, Bradaia A, Seredenina T, Inuabasi L, Osborne GF, Wadel K, Touller C, Butler R, Robertson J, Franklin SA, Smith DL, Park L, Marks PA, Wanker EE, Olson EN, Luthi-Carter R, van der Putten H, Beaumont V, Bates GP