Journal Article

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

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

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Age / Animals / Biomedical research / Brain-Derived Neurotrophic Factor - genetics / Brain-Derived Neurotrophic Factor - metabolism / Cerebral Cortex - enzymology / Cerebral Cortex - pathology / Cytoplasm / Degeneration / Epigenesis, Genetic / Female / Gene Knockdown Techniques / Health aspects / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Histones / Huntingtin Protein / Huntington Disease - enzymology / Huntington Disease - physiopathology / Huntington Disease - therapy / Huntingtons disease / Ligands / Male / Mice / Mice, 129 Strain / Mice, Inbred C57BL / Mice, Inbred CBA / Mice, Knockout / Motor ability / Nerve Tissue Proteins - metabolism / Nervous system / Neurodegeneration / Neurons - physiology / Nuclear Proteins - metabolism / Pathogenesis / Pathology / Phenotype / Physiological aspects / Proteins / Rodents / Rotarod Performance Test / Synaptic Transmission / Transcription, Genetic