The β-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy
The β-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy
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DOI：
10.1074/jbc.m705282200
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发表时间：
2007-10-26
影响因子：
4.8
通讯作者：
Mandelkow, Eva-Maria
中科院分区：
文献类型：
--
作者：
Eckermann, Katrin;Mocanu, Maria-Magdalena;Mandelkow, Eva-Maria
神经原纤维病变是一组被称为Tau病的人类疾病的特征，其特征是由微管相关蛋白Tau形成的异常细丝在细胞内显著积聚。Tau病变伴随着Tau蛋白的异常变化，包括病理构象、体突错位、过度磷酸化和聚集，其相互依赖性尚不清楚。为了解决这些问题，我们创建了转基因小鼠系，其中全长Tau的不同变体以可调节的方式表达，允许人们在指定的时间点打开和关闭表达。Tau变体的不同之处在于六肽基序的小突变，六肽基序控制Tau采用β结构构象并因此聚集的能力。“亲聚集”突变体Delta K280源自额颞叶痴呆中观察到的一种突变，在体外可以迅速聚集，而“反聚集”突变体Delta K280/PP由于两个β -断裂脯氨酸而不能聚集。在转基因小鼠中，亲聚集的Tau诱导病理构象和预缠结聚集，即使在低表达水平，反聚集突变体也不会。这表明，在体外和体内，异常聚集主要由Tau的分子结构控制。Tau蛋白的两种变体都独立于聚集而发生错定位和过度磷酸化，这表明定位和磷酸化主要是浓度增加的结果。当Tau的表达被关闭时，这些病理变化是可逆的。促聚集的Tau蛋白导致脊椎突触的大量减少。
Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created transgenic mouse lines in which different variants of full-length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a beta-structure conformation and hence to aggregate. The "pro-aggregation" mutant Delta K280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant Delta K280/PP cannot aggregate because of two beta-breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the antiaggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses.