title: Acetylation of tau inhibits its degradation and contributes to tauopathy.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Min
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Cho
authors.forename: Yungui
authors.initials: Y
authors.lastname: Zhou
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schroeder
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Yong
authors.initials: Y
authors.lastname: Shen
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Chandrani
authors.initials: C
authors.lastname: Mukherjee
authors.forename: David
authors.initials: D
authors.lastname: Meyers
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D024801:Tauopathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D054875:Ubiquitination / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D002227:Carbazoles; D003513:Cycloheximide; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D016875:tau Proteins; D000099224:p300-CBP-Associated Factor; C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; C054369:MAPT protein, human; C447939:SIRT1 protein, human