Tau – an inhibitor of deacetylase HDAC6 function

Abstract

1These two authors contributed equally to this work.Abbreviations used: AD, Alzheimer's disease; AL, acetylated lysine; BSA, bovine serum albumin; GFP, Green Fluorescent Protein; HDAC, histone deacetylase 6; HEK, human embryonic kidney cells; MAPs, microtubule-associated proteins; NFTs, neurofibrillary tangles; PHFs, paired helical filaments. AbstractAnalysis of brain microtubule protein from patients with Alzheimer's disease showed decreased alpha tubulin levels along with increased acetylation of the alpha tubulin subunit, mainly in those microtubules from neurons containing neurofibrillary tau pathology. To determine the relationship of tau protein and increased tubulin acetylation, we studied the effect of tau on the acetylation-deacetylation of tubulin. Our results indicate that tau binds to the tubulin-deacetylase, histone deacetylase 6 (HDAC6), decreasing its activity with a consequent increase in tubulin acetylation. As expected, increased acetylation was also found in tubulin from wild-type mice compared with tubulin from mice lacking tau because of the tau-mediated inhibition of the deacetylase. In addition, we found that an excess of tau protein, as a HDAC6 inhibitor, prevents induction of autophagy by inhibiting proteasome function.

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

“…Our data on the accumulation of ac-tub heterodimers might explain controversial data in previous reports on the level of tubulin acetylation. For example, AD pathology, which displays destabilized MT, was classically linked with a reduction of ac-tub 42 , whereas a more recent study on tau interaction with HDAC6 reported an increased level of ac-tub in AD samples 43 . Our results emphasize the importance of studying MT dynamics, besides tubulin post-translational modifications, in AD conditions when considering the use of HDAC6 inhibitors as a possible therapeutic approach for AD.…”

“…Moreover, overexpression of tau was shown to increase ac-tub in fibroblasts 61 , which may be explained by tau-driven inhibition of HDAC6 (ref. 43). This gives rise to the possibility that polarized cells, such as neurons, which express high level of tau and ac-tub, may be more susceptible to changes in tau and/or tubulin levels induced by Ab in comparison with other cell types.…”

Role of tau protein on neocortical and hippocampal oscillatory patterns

“…On the other hand, tau is unevenly distributed in the mammalian brain exhibiting its highest expression over frontotemporal neocortex and hippocampus (Goedert et al, 1989;Trojanowski et al, 1989;Santa-Maria et al, 2005;McMillan et al, 2008). In vivo-tau function has also been explored in tau-deficient (tau 2/2 ) mice, although scarce differences were found when compared with their wild-type (wt) counterparts (Perez et al, 2009). Tau 2/2 animals, although phenotypically normal (Harada et al, 1994), showed a significant delay in the axonal extension of hippocampal neurons and lag in stage development (Dawson et al, 2001), which might affect both neural coordination and information flow within local-and long-range circuits.…”

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

“…Also, tau co-immunoprecipitated with HDAC6 in control and AD brain extracts. Perez et al (2009) demonstrated that an excess of tau binds to HDAC6 and decreases its deacetylase activity, and thus can act as an inhibitor of HDAC6.…”