英国Wellcome Trust Sanger研究所研究人员发现，大脑中一组蛋白和一些最常见的脑部疾病的发生相关，其中包括癫痫、抑郁症、精神分裂症、智力低下以及神经退行性疾病。有关研究5  月19  日在线发表在Molecular Systems Biology杂志上。

　　Wellcome Trust Sanger研究所基因认知计划负责人Seth Grant教授称，如此多的疾病与这些蛋白相关，是由于这些蛋白在脑细胞发挥功能时起核心作用。摒弃了一次只研究一种蛋白的传统研究方法，研究人员开发出一种新的方法，可以找到相互结合的一组蛋白。这些蛋白构成可以用显微镜观测到的“分子机器”，并在脑部搜寻神经细胞的“发动机房”——被称为“突触”的神经细胞间连接。

　　为了找到这组被称为MASCs（MAGUK Associated Signaling Complexes）的关键蛋白，研究人员引进了一种之前应用于酵母细胞的研究方法。该方法利用一个“分子钩”附着于小鼠脑细胞内一种蛋白质上。然后，研究人员抓住分子钩，将其拉出，发现它带出另外100多种蛋白。这些蛋白中包含数十种引起脑部疾病的蛋白。这100多种蛋白不仅包含许多疾病蛋白，还包含控制神经细胞间传递信息、控制学习与记忆的蛋白。

　　Grant教授称，这项研究是基础科学和临床科学的重要结合。这一发现表明，分子机器本身是许多重要脑部疾病的根源。这也是一个全新的研究项目，通过探求学习和记忆的基本机制，将有助于了解大脑内部是如何运作。

　　推荐原始出处：

　　Molecular Systems Biology 5 Article number: 269  doi:10.1038/msb.2009.27

　　Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins

　　Esperanza Fernández1, Mark O Collins2, Rachel T Uren1, Maksym V Kopanitsa1, Noboru H Komiyama1, Mike D R Croning1, Lysimachos Zografos3, J Douglas Armstrong3, Jyoti S Choudhary2 & Seth G N Grant1

　　1 Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Cambridge, UK

　　2 Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge, UK

　　3 School of Informatics, Edinburgh University, Edinburgh, UK

　　The molecular complexity of mammalian proteomes demands new methods for mapping the organization of multiprotein complexes. Here, we combine mouse genetics and proteomics to characterize synapse protein complexes and interaction networks. New tandem affinity purification (TAP) tags were fused to the carboxyl terminus of PSD-95 using gene targeting in mice. Homozygous mice showed no detectable abnormalities in PSD-95 expression, subcellular localization or synaptic electrophysiological function. Analysis of multiprotein complexes purified under native conditions by mass spectrometry defined known and new interactors: 118 proteins comprising crucial functional components of synapses, including glutamate receptors, K+ channels, scaffolding and signaling proteins, were recovered. Network clustering of protein interactions generated five connected clusters, with two clusters containing all the major ionotropic glutamate receptors and one cluster with voltage-dependent K+ channels. Annotation of clusters with human disease associations revealed that multiple disorders map to the network, with a significant correlation of schizophrenia within the glutamate receptor clusters. This targeted TAP tagging strategy is generally applicable to mammalian proteomics and systems biology approaches to disease.