Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation.
A defect in microtubule (MT)-based transport contributes to the neuronal toxicity observed in Huntington's disease (HD). Histone deacetylase (HDAC) inhibitors show neuroprotective effects in this devastating neurodegenerative disorder. We report here that HDAC inhibitors, including trichostatin A (TSA), increase vesicular transport of brain-derived neurotrophic factor (BDNF) by inhibiting HDAC6, thereby increasing acetylation at lysine 40 of alpha-tubulin. MT acetylation in vitro and in cells causes the recruitment of the molecular motors dynein and kinesin-1 to MTs. In neurons, acetylation at lysine 40 of alpha-tubulin increases the flux of vesicles and the subsequent release of BDNF. We show that tubulin acetylation is reduced in HD brains and that TSA compensates for the transport- and release-defect phenotypes that are observed in disease. Our findings reveal that HDAC6 inhibition and acetylation at lysine 40 of alpha-tubulin may be therapeutic targets of interest in disorders such as HD in which intracellular transport is altered.
Dompierre
Jim P
JP
Institut Curie and Centre National de la Recherche Scientifique Unité Mixte de Recherche 146, Orsay, France.
Godin
Juliette D
JD
Charrin
Bénédicte C
BC
Cordelières
Fabrice P
FP
King
Stephen J
SJ
Humbert
Sandrine
S
Saudou
Frédéric
F
D000107:Acetylation; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D018715:Microscopy, Video; D008870:Microtubules / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D022161:Transport Vesicles / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism*; D014793:Visual Cortex / Q000166:cytology / Q000378:metabolism; D000077337:Vorinostat
D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020409:Molecular Motor Proteins; D018696:Neuroprotective Agents; D014404:Tubulin; C012589:trichostatin A; D000077337:Vorinostat; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases