title: HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease.
abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.
authors.affiliation: Vesalius Research Center, VIB and K.U. Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Constantin
authors.initials: C
authors.lastname: d'Ydewalle
authors.forename: Jyothsna
authors.initials: J
authors.lastname: Krishnan
authors.forename: Driss M
authors.initials: DM
authors.lastname: Chiheb
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Pieter
authors.initials: P
authors.lastname: Vanden Berghe
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000200:Action Potentials / Q000502:physiology; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects*; D015153:Blotting, Western; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy* / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005684:Gait / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D020125:Mutation, Missense / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009469:Neuromuscular Junction / Q000473:pathology; D045442:Rotarod Performance Test; D014404:Tubulin / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D014404:Tubulin; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases