Acetylation of tau inhibits its degradation and contributes to tauopathy.
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.
Min
Sang-Won
SW
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Cho
Seo-Hyun
SH
Zhou
Yungui
Y
Schroeder
Sebastian
S
Haroutunian
Vahram
V
Seeley
William W
WW
Huang
Eric J
EJ
Shen
Yong
Y
Masliah
Eliezer
E
Mukherjee
Chandrani
C
Meyers
David
D
Cole
Philip A
PA
Ott
Melanie
M
Gan
Li
L
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
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