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HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration

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Item Type:Article
Title:HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration
Creators Name:Mielcarek, M., Landles, C., Weiss, A., Bradaia, A., Seredenina, T., Inuabasi, L., Osborne, G.F., Wadel, K., Touller, C., Butler, R., Robertson, J., Franklin, S.A., Smith, D.L., Park, L., Marks, P.A., Wanker, E.E., Olson, E.N., Luthi-Carter, R., van der Putten, H., Beaumont, V. and Bates, G.P.
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 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 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 coordination, 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 the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.
Keywords:Brain-Derived Neurotrophic Factor, Cerebral Cortex, Gene Knockdown Techniques, Genetic Epigenesis, Genetic Transcription, Histone Deacetylases, Huntington Disease, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Phenotype, Rotarod Performance Test, Synaptic Transmission, Animals, Mice
Source:PLoS Biology
Publisher:Public Library of Science
Page Range:e1001717
Date:November 2013
Official Publication:https://doi.org/10.1371/journal.pbio.1001717
PubMed:View item in PubMed

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