2012年8月23日 讯 /生物谷BIOON/ --一 在Ruhr大学Medizinisches蛋白质组学中心的Thorsten Müller博士的带领下，研究人员目前发表论文揭示了阿尔茨海默氏症患者的大脑中的异常蛋白沉积是如何破坏神经细胞之间的信号。研究人员报告说，阿尔茨海默氏症患者大脑中的异常蛋白质的沉积会破坏神经细胞之间的信号联系。在体外细胞培养中，研究人员改变了阿尔茨海默氏症APP蛋白及相关蛋白的量，然后分析这一操作是如何影响细胞中其他蛋白质的。其结果是：APP存在的量与神经递质的生成、神经细胞之间的沟通必不可少的一种酶的量有关。
蛋白质组学一次性分析细胞所有蛋白质淀粉样蛋白斑是阿尔茨海默氏病的一个特征。它们组成了所谓的淀粉样蛋白前体蛋白APP的裂解产物，APP在阿尔茨海默氏症患者大脑中是过量的。APP在健康人中扮演什么样的角色，为什么淀粉样蛋白会异常堆积扰乱正常运作的大脑，这些在很大程度上仍然不清楚。为了了解APP的功能，RUB研究人员建立了一种新的细胞模型。新的细胞只产生极少量的APP。研究人员通过质谱分析极少量APP的产生对这些细胞的其他蛋白质有什么样的影响。通过这种方法，研究人员确定APP的产生对超过2000个蛋白有影响，并确定了这些蛋白的浓度。他们正在寻找一种特定的分子，其浓度在新建成的低APP细胞中与含有正常量的APP细胞中是具有差异的。
不正常的蛋白质能够抑制神经递质的生成。Thorsten Müller说：一个候选蛋白引起了我们的注意，这就是蛋氨酸腺苷酶II，简称MAT2A。研究发现这种酶是神经递质生成的关键。低APP的细胞含有比正常量的APP细胞较少的MAT2A。为了确认“老年痴呆症蛋白质”APP和神经递质MAT2A之间的联系，该研究小组利用阿尔茨海默氏症死者和健康人的大脑组织样本。发现在阿尔茨海默氏症患者的组织中MAT2A比健康人大脑样本中要少。（生物谷：Bioon.com）
编译自：'Alzheimer protein' seems to slow down neurotransmitter production
doi:10.1074/mcp.M112.019364
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The APP family members are key players in S-adenosylmethionine formation by MAT2A and modify BACE1 and PSEN1 gene expression - relevance for Alzheimer's disease
A. Schrtter, K. Pfeiffer, F. El Magraoui, H. Platta, R. Erdmann, Helmut E. Meyer, R. Egensperger, K. Marcus, T. Müller
A central hallmark of Alzheimers disease (AD) are senile plaques mainly composed of [beta] amyloid, which is a cleavage product of the amyloid precursor protein (APP). The physiological function of APP and its family members APLP1 and APLP2 is poorly understood. In order to fill this gap, we established a cell-culture based model with simultaneous knockdown of all members of the family. A comprehensive proteome study of the APP/APLP1/APLP2 knockdown cell lysates vs. controls revealed significant protein abundance changes of more than 30 proteins. Targeted validation of selected candidates by immunoblotting supported the significant down-regulation of the methionine adenosyltransferase II, alpha (MAT2A) as well as of peroxiredoxin 4 (PRDX4) in the knockdown cells. Moreover, MAT2A was significantly down-regulated at the mRNA level as well. MAT2A catalyzes the production of S-adenosylmethionine (SAM) from methionine and ATP, which plays a pivotal role in the methylation of neurotransmitters, DNA, proteins, and lipids. MAT2A-dependent significant up-regulation of SAM was also detectable in the knockdown cells compared to controls. Our results point to a role of the APP family proteins in cellular methylation mechanisms and fit to findings of disturbed SAM levels in tissue and CSF of Alzheimer disease patients vs. controls. Importantly, methylation plays a central role for neurotransmitter generation like acetylcholine pointing to a crucial relevance of our findings for AD. In addition, we identified differential gene expression of BACE1 and PSEN1 in the knockdown cells, which is possibly a consequence of MAT2A deregulation and may indicate a self regulatory mechanism.
