Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation.

J. P. Dompierre, J. D. Godin, B. C. Charrin, F. P. Cordelieres, S. J. King, S. Humbert, F. Saudou
Journal of Neuroscience. 2007-03-28; 27(13): 3571-3583
DOI: 10.1523/jneurosci.0037-07.2007

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1. J Neurosci. 2007 Mar 28;27(13):3571-83.

Histone deacetylase 6 inhibition compensates for the transport deficit in
Huntington’s disease by increasing tubulin acetylation.

Dompierre JP(1), Godin JD, Charrin BC, Cordelières FP, King SJ, Humbert S, Saudou
F.

Author information:
(1)Institut Curie and Centre National de la Recherche Scientifique Unité Mixte de
Recherche 146, Orsay, France.

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.

DOI: 10.1523/JNEUROSCI.0037-07.2007
PMID: 17392473 [Indexed for MEDLINE]

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