Histone deacetylase 6 interacts with the microtubule-associated protein tau

Authors


Address correspondence and reprint requests to Gail V. W. Johnson, PhD, 601 Elmwood Avenue, Box 604, Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
E-mail: gail_johnsonvoll@urmc.rochester.edu

Abstract

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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