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Title: HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease
Authors: van Outryve d'Ydewalle, Constantin
Krishnan, Jyothsna
Chiheb, Driss
Van Damme, Philip
Irobi, Joy
Kozikowski, Alan P
Vanden Berghe, Pieter
Timmerman, Vincent
Robberecht, Wim
Van Den Bosch, Ludo # ×
Issue Date: Jul-2011
Publisher: Nature Pub. Co.
Series Title: Nature Medicine vol:17 issue:8 pages:968-974
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.
ISSN: 1078-8956
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group Experimental Neurology
Laboratory for Neurobiology (Vesalius Research Center)
Laboratory for Signal Integration in Cell Fate Decision
Translational Research in GastroIntestinal Disorders
× corresponding author
# (joint) last author

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