Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 13, Pages 3571-3583Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0037-07.2007
Keywords
Huntington's disease; polyglutamine; transport; microtubules; BDNF; neuroprotection
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Funding
- NIMH NIH HHS [MH/NS 31862] Funding Source: Medline
- NINDS NIH HHS [R01 NS048501, NS 48501] Funding Source: Medline
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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.
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