Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression data from cortex of 15 week old wild type, R6/2, HDAC4het and R6/2::HDAC4het mice


ABSTRACT: 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 (http://race.unil.ch).

ORGANISM(S): Mus musculus

SUBMITTER: Tamara Seredenin 

PROVIDER: E-GEOD-38219 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications


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 in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed c  ...[more]

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