한빛사논문, 상위피인용논문
Abstract
Sang-Won Min,1,3 Seo-Hyun Cho,1,3 Yungui Zhou,1 Sebastian Schroeder,2,4 Vahram Haroutunian,10 William W. Seeley,3 Eric J. Huang,5 Yong Shen,9 Eliezer Masliah,7 Chandrani Mukherjee,8 David Meyers,8 Philip A. Cole,8 Melanie Ott,2,4 and Li Gan1,3,6,*
1Gladstone Institute of Neurological Disease
2Gladstone Institute of Virology and Immunology
San Francisco, CA 94158, USA
3Department of Neurology
4Department of Medicine
5Department of Pathology
6Biomedical Science and Neuroscience Graduate Program
University of California, San Francisco, CA 94143, USA
7Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093, USA
8Department of Pharmacology and Molecular Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
9Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA
10Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY 10468, USA
*Correspondence
DOI 10.1016/j.neuron.2010.08.044
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). 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.
Erratum
http://www.cell.com/neuron/fulltext/S0896-6273(10)00929-3
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