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首页> 外文期刊>Neuron >Acetylation of tau inhibits its degradation and contributes to tauopathy.
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Acetylation of tau inhibits its degradation and contributes to tauopathy.

机译：tau的乙酰化抑制其降解并促进tauopathy。

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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.
机译：以tau蛋白磷酸化为特征的神经退行性变态病包括额颞叶痴呆和与17号染色​​体（FTDP-17）和阿尔茨海默氏病（AD）相关的帕金森氏病。降低tau含量可改善AD和FTDP-17小鼠模型的认知功能，但调节致病tau转换的机制尚不清楚。我们发现tau被乙酰化，tau乙酰化阻止了磷酸化tau（p-tau）的降解。我们生成了两种对乙酰化tau特异的抗体，结果表明在tauopathy的早期和中度Braak阶段，tau乙酰化水平升高。组蛋白乙酰转移酶p300参与tau乙酰化，III类蛋白质脱乙酰酶SIRT1参与脱乙酰。删除SIRT1可能会通过阻止蛋白酶体介导的降解来提高乙酰化tau蛋白和p-tau蛋白致病性形式的水平。用小分子抑制p300可以促进tau脱乙酰化并消除与tauopathy有关的p-tau。调节tau乙酰化可能是减少tau介导的神经变性的新治疗策略。

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