title: Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Bobrowska
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
mesh_terms: D000107:Acetylation; D000328:Adult; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014404:Tubulin; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases