Müller Thorsten, Schrötter Andreas, Loosse Christina, Pfeiffer Kathy, Theiss Carsten, Kauth Marion, Meyer Helmut E, Marcus Katrin
Functional Proteomics, Medizinisches Proteom-Center, Ruhr-University Bochum, D-44801 Bochum, Germany.
Biochim Biophys Acta. 2013 Jan;1834(1):387-94. doi: 10.1016/j.bbapap.2012.07.017. Epub 2012 Aug 7.
The ternary complex consisting of AICD/FE65/TIP60 is thought to play a role in gene expression and was suggested to have a crucial impact in Alzheimer's disease. AICD is the intracellular subdomain of the amyloid precursor protein (APP) and able to bind the adapter protein FE65 and the histone acetyltransferase TIP60 setting up a nuclear dot-like phenotype. Within this work we readdressed the generation of the complex as a function of its compartments. Subsequently, we studied the proteome of AFT expressing cells vs. controls and identified Stathmin1 significantly down-regulated in AFT cells. Stathmin1 functions as an important regulatory protein of microtubule dynamics and was found associated with neurofibrillary tangles in brains of Alzheimer's disease patients. We validated our results using an independent label-free mass spectrometry based method using the same cell culture model. In a reversal model with diminished APP expression, caused by simultaneous knock-down of all three members of the APP family, we further confirmed our results, as Stathmin1 was regulated in an opposite fashion. We hypothesize that AICD-dependent deregulation of Stathmin1 causes microtubule disorganization, which might play an important role for the pathophysiology of Alzheimer's disease.
由AICD/FE65/TIP60组成的三元复合物被认为在基因表达中起作用，并被认为对阿尔茨海默病有至关重要的影响。AICD是淀粉样前体蛋白（APP）的细胞内亚结构域，能够结合衔接蛋白FE65和组蛋白乙酰转移酶TIP60，形成核点状表型。在这项工作中，我们重新探讨了该复合物的生成与其区室的关系。随后，我们研究了表达AFT的细胞与对照细胞的蛋白质组，发现Stathmin1在AFT细胞中显著下调。Stathmin1作为微管动力学的重要调节蛋白，在阿尔茨海默病患者大脑中与神经原纤维缠结有关。我们使用相同的细胞培养模型，通过一种基于无标记质谱的独立方法验证了我们的结果。在由APP家族所有三个成员同时敲低导致APP表达减少的反向模型中，我们进一步证实了我们的结果，因为Stathmin1的调节方式相反。我们推测，AICD依赖的Stathmin1失调导致微管紊乱，这可能在阿尔茨海默病的病理生理学中起重要作用。
