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A12 HDAC4 interacts with huntington and HDAC4 reduction decreases cytoplamsic aggregation and rescues synaptic dysfunction in HD mouse models
  1. M Mielcarek1,
  2. C Landles1,
  3. A Weiss2,
  4. A Bradaia3,
  5. T Seredenina4,
  6. L Inuabasi1,
  7. K Wadel3,
  8. C Touller3,
  9. R Butler1,
  10. J Robertson1,
  11. SA Franklin1,
  12. DL Smith1,
  13. L Park5,
  14. PA Marks6,
  15. EE Wanker7,
  16. EN Olson8,
  17. R Luthi-Carter4,
  18. H van der Putten2,
  19. V Beaumont5,
  20. GP Bates1
  1. 1Department of Medical and Molecular Genetics, King's College London, London, UK
  2. 2Novartis Institutes for BioMedical Research, Basel, Switzerland
  3. 3Department of Neuroservice, France
  4. 4Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
  5. 5CHDI Foundation, Los Angeles, California, USA
  6. 6Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  7. 7Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  8. 8Department of Molecular Biology, Southwestern University, Dallas, Texas, USA

Abstract

Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We have found that HDAC4 associates with mutant exon-1 and full length HTT in vivo in a polyQ length-dependent manner and co-localises predominantly with cytoplasmic inclusions in the brains of HD mouse models. HDAC4 knock-down inhibited aggregate formation in both the R6/2 (N-terminal fragment) and HdhQ150 (full length knock-in) mouse models of HD. This reduction in aggregation occurred in the cytoplasm, consistent with the subcellular localisation of HDAC4 in mouse brain, and was associated with a restoration of synaptic function. There was no evidence for HDAC4 translocation to the nucleus during disease progression, HDAC4 knock-down had no effect on HTT aggregation in the nucleus and no impact on global transcriptional dysregulation. Knock-down of HDAC4 improved motor co-ordination, as determined by rotarod performance, neurological phenotypes and extended survival. This provides a clear demonstration that cytoplasmic pathogenic mechanisms contribute to HD-related neurodegenerative phenotypes and identifies HDAC4 as a therapeutic target for HD. Our demonstration that the administration of SAHA decreases HDAC4 protein but not Hdac4 mRNA in vivo indicates that HDAC4 provides a mechanism of targeting mutant HTT that is amenable to small molecule therapeutics.

  • HDAC4
  • HTT aggregation
  • synaptic dysfunction
  • cytoplasmic pathophysiology

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