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

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.

• Authors: 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 Beaumont, Gillian P Bates
• Journal: PLoS biology (PLoS Biol) Vol. 11 Issue 11 Pg. e1001717 (Nov 2013) ISSN: 1545-7885 [Electronic] United States
• PMID: 24302884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Brain-Derived Neurotrophic Factor (genetics, metabolism)
• Cerebral Cortex (enzymology, pathology)
• Epigenesis, Genetic
• Female
• Gene Knockdown Techniques
• Histone Deacetylases (genetics, metabolism)
• Huntingtin Protein
• Huntington Disease (enzymology, physiopathology, 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