Acetylation of tau inhibits its degradation and contributes to tauopathy

Sang Won Min, Seo Hyun Cho, Yungui Zhou, Sebastian Schroeder, Vahram Haroutunian, William W. Seeley, Eric J. Huang, Yong Shen, Eliezer Masliah, Chandrani Mukherjee, David Meyers, Philip A. Cole, Melanie Ott, Li Gan

Research output: Contribution to journalArticlepeer-review

Abstract

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). We generated two antibodies specific for acetylated tau and 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, probably 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.

Original languageEnglish (US)
Pages (from-to)953-966
Number of pages14
JournalNeuron
Volume67
Issue number6
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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