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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / pathology
  • Epigenesis, Genetic
  • Female
  • Gene Knockdown Techniques
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Huntingtin Protein
  • Huntington Disease / enzymology*
  • Huntington Disease / physiopathology
  • Huntington Disease / therapy
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism*
  • Neurons / physiology
  • Nuclear Proteins / metabolism*
  • Phenotype
  • Rotarod Performance Test
  • Synaptic Transmission
  • Transcription, Genetic

Substances

  • Brain-Derived Neurotrophic Factor
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Hdac5 protein, mouse
  • Histone Deacetylases

Grant support

This work was supported by grants from the CHDI Foundation and Huntington's Disease Society of America (HDSA) to GB and from the DFG (SFB740 and SFB618), BMBF (NGFN-Plus, NeuroNet), HDSA, and the Helmholtz Association (MSBN, HelMA) to EEW. With the exception of the CHDI Foundation, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CHDI Foundation is a not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. The research at Neuroservice was conducted under a fee-for-service agreement for CHDI Foundation. Research conducted at King's College was performed in collaboration with and funded by the CHDI Foundation. In is case, the funder, through CHDI Management, fully participated in study design, data collection and analysis, the decision to publish, and preparation of the manuscript.