HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration

Michal Mielcarek, Christian Landles, Andreas Weiss, Amyaouch Bradaia, Tamara Seredenina, Linda Inuabasi, Georgina F. Osborne, Kristian Wadel, Chrystelle Touller, Rachel Butler, Janette Robertson, Sophie A. Franklin, Donna L. Smith, Larry Park, Paul A. Marks, Erich E. Wanker, Eric N. Olson, Ruth Luthi-Carter, Herman van der Putten, Vahri BeaumontGillian P. Bates

Research output: Contribution to journalArticle

92 Scopus citations

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.

Original languageEnglish (US)
Article numbere1001717
JournalPLoS biology
Volume11
Issue number11
DOIs
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Fingerprint Dive into the research topics of 'HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration'. Together they form a unique fingerprint.

  • Cite this

    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., ... Bates, G. P. (2013). HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration. PLoS biology, 11(11), [e1001717]. https://doi.org/10.1371/journal.pbio.1001717