title: 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.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Michal
authors.initials: M
authors.lastname: Mielcarek
authors.forename: Christian
authors.initials: C
authors.lastname: Landles
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaia
authors.forename: Tamara
authors.initials: T
authors.lastname: Seredenina
authors.forename: Linda
authors.initials: L
authors.lastname: Inuabasi
authors.forename: Georgina F
authors.initials: GF
authors.lastname: Osborne
authors.forename: Kristian
authors.initials: K
authors.lastname: Wadel
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Touller
authors.forename: Rachel
authors.initials: R
authors.lastname: Butler
authors.forename: Janette
authors.initials: J
authors.lastname: Robertson
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Franklin
authors.forename: Donna L
authors.initials: DL
authors.lastname: Smith
authors.forename: Larry
authors.initials: L
authors.lastname: Park
authors.forename: Paul A
authors.initials: PA
authors.lastname: Marks
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Herman
authors.initials: H
authors.lastname: van der Putten
authors.forename: Vahri
authors.initials: V
authors.lastname: Beaumont
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D045442:Rotarod Performance Test; D009435:Synaptic Transmission; D014158:Transcription, Genetic
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases