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PLoS Biol. 2013 Nov;11(11):e1001717. doi: 10.1371/journal.pbio.1001717. Epub 2013 Nov 26.

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

Author information

1
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.

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.

PMID:
24302884
PMCID:
PMC3841096
DOI:
10.1371/journal.pbio.1001717
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Andreas Weiss and Herman van der Putten are employees of Novartis AG and potentially own shares in the company. Neuroservice conducted the research through a fee-for-service agreement for the CHDI Foundation. Larry Park and Vahri Beaumont are employed by CHDI Management Inc. to provide consulting services to CHDI Foundation. Amyaouch Bradaia, Kristian Wadel, and Chrystelle Touller are employees of Neuroservice. There are no patents, products in development, or marketed products to declare. We fully adhere to all the PLoS Biology policies on sharing data and materials, as detailed online in the guide for authors.

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