Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate.
Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate.
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DOI：
10.1093/brain/aww137
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Hanger DP
中科院分区：
文献类型：
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作者：
Bondulich MK;Guo T;Meehan C;Manion J;Rodriguez Martin T;Mitchell JC;Hortobagyi T;Yankova N;Stygelbout V;Brion JP;Noble W;Hanger DP
tau蛋白的翻译后修饰在人类tau蛋白病中很常见。Bondulich等人产生了表达低水平的与人tau蛋白病相关的截短形式的tau（Tau 35）的转基因小鼠。Tau 35小鼠发生进行性tau神经病理学和认知障碍，模拟人类疾病。批准的药物4-苯基丁酸酯挽救这些异常。tau蛋白的翻译后修饰在人类tau蛋白病中很常见。Bondulich等人产生了表达低水平的与人tau蛋白病相关的截短形式的tau（Tau 35）的转基因小鼠。Tau 35小鼠发生进行性tau神经病理学和认知障碍，模拟人类疾病。批准的药物4-苯丁酸酯挽救这些异常。人神经退行性tau蛋白病在脑中表现出病理性tau聚集体，沿着有不同的临床特征，包括认知和运动功能障碍。翻译后修饰包括磷酸化、泛素化和截短，是人tau蛋白病中脑中存在的tau蛋白的特征性特征。我们以前曾报道过一种N-末端截短形式的tau蛋白在人脑中与tau蛋白病的发展有关，并且高度磷酸化。我们已经产生了一种新的小鼠tau蛋白病模型，其中这种人脑衍生的35 kDa tau片段（Tau 35）在没有任何突变的情况下表达，并在人tau启动子的控制下。大多数现有的tau蛋白病小鼠模型以在人类神经退行性疾病中不发生的水平过表达突变tau蛋白，而Tau 35转基因表达相当于内源性小鼠tau蛋白表达的不到10%。Tau 35小鼠概括了人类tau蛋白病的关键特征，包括聚集和异常磷酸化的tau蛋白、进行性认知和运动缺陷、自噬/溶酶体功能障碍、突触蛋白损失和寿命缩短。重要的是，我们发现，4-苯基丁酸钠（Buphenyl®），一种用于治疗尿素循环障碍的药物，目前在一系列神经退行性疾病的临床试验中，逆转了在Tau 35小鼠中观察到的tau和自噬异常，行为缺陷和突触蛋白1丢失。我们的研究结果首次表明，与其他tau转基因小鼠模型不同，Tau 35小鼠中人类疾病相关tau片段的最小表达导致了深刻的和进行性的tau蛋白病和认知变化，这些变化通过使用临床批准的药物进行药理学干预来挽救。因此，这些新的Tau 35小鼠代表了一种高度疾病相关的动物模型，在其中研究分子机制并开发用于人类tau蛋白病的新治疗方法。
Post-translational modification of tau is common in human tauopathies. Bondulich et al. generate transgenic mice expressing low levels of a truncated form of tau (Tau35) that is associated with human tauopathy. Tau35 mice develop progressive tau neuropathology and cognitive impairment, modelling human disease. The approved drug 4-phenylbutyrate rescues these abnormalities. Post-translational modification of tau is common in human tauopathies. Bondulich et al. generate transgenic mice expressing low levels of a truncated form of tau (Tau35) that is associated with human tauopathy. Tau35 mice develop progressive tau neuropathology and cognitive impairment, modelling human disease. The approved drug 4-phenylbutyrate rescues these abnormalities. Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications including phosphorylation, ubiquitination and truncation, are characteristic features of tau present in the brain in human tauopathy. We have previously reported an N-terminally truncated form of tau in human brain that is associated with the development of tauopathy and is highly phosphorylated. We have generated a new mouse model of tauopathy in which this human brain-derived, 35 kDa tau fragment (Tau35) is expressed in the absence of any mutation and under the control of the human tau promoter. Most existing mouse models of tauopathy overexpress mutant tau at levels that do not occur in human neurodegenerative disease, whereas Tau35 transgene expression is equivalent to less than 10% of that of endogenous mouse tau. Tau35 mice recapitulate key features of human tauopathies, including aggregated and abnormally phosphorylated tau, progressive cognitive and motor deficits, autophagic/lysosomal dysfunction, loss of synaptic protein, and reduced life-span. Importantly, we found that sodium 4-phenylbutyrate (Buphenyl®), a drug used to treat urea cycle disorders and currently in clinical trials for a range of neurodegenerative diseases, reverses the observed abnormalities in tau and autophagy, behavioural deficits, and loss of synapsin 1 in Tau35 mice. Our results show for the first time that, unlike other tau transgenic mouse models, minimal expression of a human disease-associated tau fragment in Tau35 mice causes a profound and progressive tauopathy and cognitive changes, which are rescued by pharmacological intervention using a clinically approved drug. These novel Tau35 mice therefore represent a highly disease-relevant animal model in which to investigate molecular mechanisms and to develop novel treatments for human tauopathies.