Histone deacetylase 6 interacts with the microtubule‐associated protein tau

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.

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…57), in fact TSA treatment leads to dramatic accumulation of ac-tau, and ac-tau was found in NFTs in various neurodegenerative diseases 16,17 . Phosphorylation of tau, a modification of tau that underlies tau-mediated degeneration, and that was shown to impair synaptic function at preclinical stages of disease 58 , has been associated with this acetylation state.…”

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…In contrast, HDAC6 regulates microtubule function and stability via tubulin acetylation (Guan et al, 2009;Hubbert et al, 2002), and dampening HDAC6 activity promotes tau and Aβ clearance (Cook et al, 2012;Sung et al, 2012;Zhang et al, 2014). Notably, HDAC2 and HDAC6 are overexpressed in the cortex and hippocampus of AD patients, although the cause and effect of this upregulation remains unknown (Ding et al, 2008;Graff et al, 2012).…”

“…The 18 known HDAC isoforms are divided into four classes (I-IV) and it is not fully clear which HDAC isoforms might be involved in the therapeutic effects of pan-HDACis observed in AD models. Class I HDAC and HDAC6 have been implicated in AD memory-related dysfunction (Ding et al, 2008;Guan et al, 2009), and among class I, HDAC2 and HDAC3 are critical to control multiple memory-related genes. Indeed, these enzymes have been described as negative regulators of memory consolidation (Guan et al, 2009;McQuown et al, 2011).…”

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

“…The association of HDAC6 with tau was shown in cell culture models and in human brain tissue, and was potentiated after proteasomal inhibition (Ding et al, 2008). HDAC6 interacts via its SE14 region with the MTbinding domain of tau, an interaction that is neither dependent on the deacetylase activity nor on the UBP binding domain of HDAC6.…”