Acetylation of tau inhibits its degradation and contributes to tauopathy.
Acetylation of tau inhibits its degradation and contributes to tauopathy.
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DOI：
10.1016/j.neuron.2010.08.044
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发表时间：
2010-09-23
期刊：
影响因子：
16.2
通讯作者：
Gan, Li
中科院分区：
文献类型：
--
作者：
Min, Sang-Won;Cho, Seo-Hyun;Zhou, Yungui;Schroeder, Sebastian;Haroutunian, Vahram;Seeley, William W.;Huang, Eric J.;Shen, Yong;Masliah, Eliezer;Mukherjee, Chandrani;Meyers, David;Cole, Philip A.;Ott, Melanie;Gan, Li
以过度磷酸化tau为特征的神经退行性疾病包括额颞部痴呆、17号染色体相关帕金森症(FTDP-17)和阿尔茨海默病(AD)。降低tau水平可改善AD和FTDP-17模型小鼠的认知功能，但调节致病tau周转的机制尚不清楚。我们发现tau是乙酰化的，并且tau的乙酰化阻止了磷酸化tau(p-tau)的降解。使用两种针对乙酰化tau的抗体，我们发现tau乙酰化在tau病的早期和中期Braak阶段的患者中升高。组蛋白乙酰转移酶p300参与tau乙酰化，III型蛋白去乙酰化酶SIRT1参与脱乙酰化。删除SIRT1可增强体内乙酰化tau和致病形式的p-tau的水平，可能是通过阻止蛋白酶体介导的降解。用小分子抑制p300可促进tau脱乙酰化，消除与tau病相关的p-tau。调节tau乙酰化可能成为减少tau介导的神经变性的一种新的治疗策略。
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). Using two antibodies specific for acetylated tau, we 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 in vivo, likely 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.
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