Acetylation of tau inhibits its degradation and contributes to tauopathy.

TitleAcetylation of tau inhibits its degradation and contributes to tauopathy.
Publication TypeJournal Article
Year of Publication2010
AuthorsMin S-W, Cho S-H, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L
Date Published2010 Sep 23
KeywordsAcetylation, Analysis of Variance, Animals, Animals, Newborn, Carbazoles, Cells, Cultured, Cerebral Cortex, Cycloheximide, Disease Models, Animal, Enzyme Inhibitors, Gene Expression Regulation, Humans, Immunoprecipitation, Mice, Mice, Transgenic, Models, Biological, Mutation, Neurons, p300-CBP Transcription Factors, Phosphorylation, Protein Synthesis Inhibitors, Rats, Rats, Sprague-Dawley, Sirtuin 1, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, tau Proteins, Tauopathies, Time Factors, Transfection, Ubiquitination

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.

Alternate JournalNeuron
PubMed ID20869593
PubMed Central IDPMC3035103
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States
AG023501-06 / AG / NIA NIH HHS / United States
R01 AG030207-01A2 / AG / NIA NIH HHS / United States
R01 AG030207 / AG / NIA NIH HHS / United States
P50 AG023501-01 / AG / NIA NIH HHS / United States