Journal
JOURNAL OF NEUROCHEMISTRY
Volume 106, Issue 5, Pages 2119-2130Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2008.05564.x
Keywords
Alzheimer's disease; phosphorylation; protein accumulation; tubacin; tubulin deacetylation
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Funding
- NIA NIH HHS [P50 AG16582, P50 AG016582] Funding Source: Medline
- NINDS NIH HHS [R01 NS051279, NS051279, R01 NS051279-04] Funding Source: Medline
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Histone deacetylase 6 (HDAC6), a unique cytoplasmic deacetylase, likely plays a role in neurodegeneration by coordinating cell responses to abnormal protein aggregation. Here, we provide in vitro and in vivo evidence that HDAC6 interacts with tau, a microtubule-associated protein that forms neurofibrillary tangles in Alzheimer's disease. This interaction is mediated by the microtubule-binding domain on tau and the Ser/Glu tetradecapeptide domain on HDAC6. Treatment with tubacin, a selective inhibitor of tubulin deacetylation activity of HDAC6, did not disrupt HDAC6-tau interaction. Nonetheless tubacin treatment attenuated site-specific tau phosphorylation, as did shRNA-mediated knockdown of HDAC6. Proteasome inhibition potentiated HDAC6-tau interactions and facilitated the concentration and co-localization of HDAC6 and tau in a perinuclear aggresome-like compartment, independent of HDAC6 tubulin deacetylase activity. Furthermore, we observed that in Alzheimer's disease brains the protein level of HDAC6 was significantly increased. These findings establish HDAC6 as a tau-interacting protein and as a potential modulator of tau phosphorylation and accumulation.
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