Increased acetylation of microtubules rescues human tau-induced microtubule defects and neuromuscular junction abnormalities in Drosophila.
Increased acetylation of microtubules rescues human tau-induced microtubule defects and neuromuscular junction abnormalities in Drosophila.
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微管乙酰化的增加可挽救果蝇中人 tau 诱导的微管缺陷和神经肌肉接头异常
DOI：
10.1242/dmm.028316
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发表时间：
2017-10-01
影响因子：
4.3
通讯作者：
Zhang YQ
中科院分区：
文献类型：
--
作者：
Mao CX;Wen X;Jin S;Zhang YQ
Tau通常与微管（MT）结合并稳定微管（MT），但在阿尔茨海默病和相关的神经退行性疾病中过度磷酸化并聚集成神经元缠结，这些疾病统称为Tau病。MT受不同形式的翻译后修饰（包括乙酰化）调控;乙酰化MT代表更稳定的微管群体。在我们以前的研究中，我们表明，抑制组蛋白脱乙酰酶6（HDAC 6），使微管蛋白在赖氨酸40处脱乙酰化，挽救了由tau蛋白过表达引起的MT和神经肌肉接头生长缺陷。然而，HDAC 6还作用于参与与微管蛋白无关的不同生物过程的其他蛋白质。为了直接检查增加的微管蛋白乙酰化对tau毒性的作用，我们通过CRISPR/Cas9技术产生了定点α-微管蛋白K40 Q突变以模拟乙酰化的MT，并发现乙酰化模拟α-微管蛋白挽救了tau诱导的MT缺陷和神经肌肉接头发育异常。我们还表明，ACY-1215和tubastatin A（HDAC 6的两种有效和选择性抑制剂）的后期给药在异常已经变得明显之后挽救了tau诱导的MT缺陷。总体而言，我们的研究结果表明，通过基因操作或药物增加MT乙酰化可能被用作干预tau蛋白病的潜在策略。突出显示的文章：通过遗传和药理学方法增加微管的乙酰化拯救了果蝇肌肉和神经元中人类tau蛋白过表达诱导的毒性。
ABSTRACT Tau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification, including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we showed that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression. However, HDAC6 also acts on other proteins that are involved in distinct biological processes unrelated to tubulins. In order to examine directly the role of increased tubulin acetylation against tau toxicity, we generated a site-directed α-tubulinK40Q mutation by CRISPR/Cas9 technology to mimic the acetylated MTs and found that acetylation-mimicking α-tubulin rescued tau-induced MT defects and neuromuscular junction developmental abnormalities. We also showed that late administration of ACY-1215 and tubastatin A, two potent and selective inhibitors of HDAC6, rescued the tau-induced MT defects after the abnormalities had already become apparent. Overall, our results indicate that increasing MT acetylation by either genetic manipulations or drugs might be used as potential strategies for intervention in tauopathies. Highlighted Article: Increased acetylation of microtubules by genetic and pharmacological approaches rescues human tau overexpression-induced toxicity in Drosophila muscles and neurons.
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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
4.7
作者：
Ding H;Dolan PJ;Johnson GV
通讯作者：
Johnson GV
在嗜热四膜虫中，赖氨酸40在α-微管蛋白中的乙酰化并不是必需的。
影响因子：
7.8
作者：
GAERTIG, J;CRUZ, MA;BOWEN, J;GU, L;PENNOCK, DG;GOROVSKY, MA
通讯作者：
GOROVSKY, MA
影响因子：
3.3
作者：
Aguilar A;Becker L;Tedeschi T;Heller S;Iomini C;Nachury MV
通讯作者：
Nachury MV
影响因子：
56.9
作者：
Jinek, Martin;Chylinski, Krzysztof;Charpentier, Emmanuelle
通讯作者：
Charpentier, Emmanuelle