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The Journal of Neuroscience, March 28, 2007, 27(13):3571-3583; doi:10.1523/JNEUROSCI.0037-07.2007

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Neurobiology of Disease
Histone Deacetylase 6 Inhibition Compensates for the Transport Deficit in Huntington's Disease by Increasing Tubulin Acetylation

Jim P. Dompierre,^1,2 * Juliette D. Godin,^1,2 * Bénédicte C. Charrin,^1,2 Fabrice P. Cordelières,^1,2,3 Stephen J. King,⁴ Sandrine Humbert,^1,2 and Frédéric Saudou^1,2,3

¹Institut Curie, ²Centre National de la Recherche Scientifique Unité Mixte de Recherche 146, and ³Plate-forme Imagerie Cellulaire et Tissulaire, F-91405 Orsay, France, and ⁴Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri 64110

Correspondence should be addressed to either of the following: Sandrine Humbert, Institut Curie, Unité Mixte de Recherche (UMR) 146, F-91405 Orsay, France, Email: Sandrine.Humbert{at}curie.u-psud.fr; or Frederic Saudou, Institut Curie, UMR 146, F-91405 Orsay, France, Email: Frederic.Saudou{at}curie.u-psud.fr

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 -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 -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 -tubulin may be therapeutic targets of interest in disorders such as HD in which intracellular transport is altered.

Key words: Huntington's disease; polyglutamine; transport; microtubules; BDNF; neuroprotection

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Received Jan. 5, 2007; revised Feb. 19, 2007; accepted Feb. 22, 2007.

Correspondence should be addressed to either of the following: Sandrine Humbert, Institut Curie, Unité Mixte de Recherche (UMR) 146, F-91405 Orsay, France, Email: Sandrine.Humbert{at}curie.u-psud.fr; or Frederic Saudou, Institut Curie, UMR 146, F-91405 Orsay, France, Email: Frederic.Saudou{at}curie.u-psud.fr

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