Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy

Abstract

Summary Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated and that tau acetylation prevents degradation of phosphorylated tau (p-tau). Using two antibodies specific for acetylated tau, we showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy. Histone acetyltransferase p300 was involved in tau acetylation and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau in vivo, likely by blocking proteasome-mediated degradation. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Modulating tau acetylation could be a new therapeutic strategy to reduce tau-mediated neurodegeneration.

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.…”

“…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. Indeed, tau acetylation was shown to prevent the degradation of phosphorylated tau 17 . Both forms have impaired MT binding, which results in further MT instability 16 .…”

“…In the light of a recent study showing that HDAC6, in addition to SIRT1 (ref. 17), also deacetylates tau 16 , we analysed the level of ac-tau on Ab treatment. After exposure of neurons to 100 nM, or 1 mM Ab or 100 nM TSA, tau immunoprecipitated from neuronal lysates showed increased acetylation (Fig.…”

“…Recently, tau was demonstrated to be acetylated in the microtubule (MT)-binding domain, a post-translational modification that impairs the binding of tau to MTs, and acetylated tau (ac-tau) was specifically found in tau aggregates in AD and related tauopathies 16,17 . Histone deacetylase 6 (HDAC6), a cytosolic member of class II HDACs 18 , is responsible for deacetylating both tubulin 19 and tau 16 .…”

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…In addition to modulating transcription factors and metabolic enzymes, SIRT1 has been shown to directly deacetylate proteins that impact neurodegenerative disorders (Herskovits & Guarente, 2014; Min et al, 2010; Montie, Pestell, & Merry, 2011). Studies using resveratrol, a polyphenolic compound that activates SIRT1 and other targets, have shown mixed effects in the SOD1 G93A mouse model of ALS, with some dosing regimens showing protection and others indicating no effect on disease progression (Han, Choi, Soon Shin, & Kang, 2012; Kim et al, 2007; Mancuso et al, 2014; Markert, Kim, Gifondorwa, Childers, & Milligan, 2010; Song, Chen, & Zhang, 2014).…”