A Caenorhabditis elegans model of tau hyperphosphorylation: Induction of developmental defects by transgenic overexpression of Alzheimer's disease-like modified tau
A Caenorhabditis elegans model of tau hyperphosphorylation: Induction of developmental defects by transgenic overexpression of Alzheimer's disease-like modified tau
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DOI：
10.1016/j.neurobiolaging.2007.05.011
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发表时间：
2009-01-01
影响因子：
4.2
通讯作者：
Hutter, Harald
中科院分区：
文献类型：
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作者：
Brandt, Roland;Gergou, Aikaterini;Hutter, Harald
微管相关的tau蛋白在阿尔茨海默病（AD）中变得功能和结构改变。为了分析tau修饰及其在非脊椎动物模型中的作用，我们产生了具有人tau的泛神经元表达的转基因秀丽隐杆线虫菌株和模拟AD相关tau修饰的假过度磷酸化（PHP）tau构建体。我们表明，人类tau蛋白在C。elegans变得高度磷酸化并表现出与PHP tau和人PHF tau相似的构象变化。这两个，野生型tau和PHP tau诱导一个渐进的年龄依赖性发展的表型不协调运动（unc）的神经元变性的情况下。然而，只有PHP tau诱导运动神经元发育的缺陷模式，如在背索中存在间隙所示。错侧连合和轴突局部增宽。数据表明，C. Elgans能够将人tau高度磷酸化为AD样状态，而只有稳定的疾病样tau修饰诱导发育缺陷，这表明病理性tau对轴突生长和寻路的细胞内机制的特异性干扰。(C)2007爱思唯尔公司All rights reserved.
The microtubule-associated tau proteins become functionally and structurally altered in Alzheimer's disease (AD). To analyze tau modification and its role in a non-vertebrate animal model, we produced transgenic Caenorhabditis elegans strains with a panneuronal expression of human tau and a pseudohyperphosphorylated (PHP) tau construct that mimics AD-relevant tau modification. We show that human tau in C. elegans becomes highly phosphorylated and exhibits conformational changes similar to PHP tau and human PHF tau. Both, wt tau and PHP tau induced a progressive age-dependent development of a phenotype of uncoordinated locomotion (unc) in the absence of neuronal degeneration. However, only PHP tau induced a defective pattern of motor neuron development as indicated by the presence of gaps in the dorsal cord. commissures on the wrong side and local broadening of axons. The data indicate that C. elgans is capable of highly phosphorylating human tau to an AD-like state whereas only stable disease-like tau modification induce developmental defects suggesting a specific interference of pathologic tau with intracellular mechanisms of axonal out-growth and pathfinding. (C) 2007 Elsevier Inc. All rights reserved.