英國Wellcome Trust Sanger研究所研究人員發(fā)現(xiàn),，大腦中一組蛋白和一些最常見的腦部疾病的發(fā)生相關(guān),，其中包括癲癇,、抑郁癥,、精神分裂癥,、智力低下以及神經(jīng)退行性疾病,。有關(guān)研究5 月19 日在線發(fā)表在Molecular Systems Biology雜志上。
Wellcome Trust Sanger研究所基因認(rèn)知計劃負(fù)責(zé)人Seth Grant教授稱,，如此多的疾病與這些蛋白相關(guān),，是由于這些蛋白在腦細(xì)胞發(fā)揮功能時起核心作用。摒棄了一次只研究一種蛋白的傳統(tǒng)研究方法,，研究人員開發(fā)出一種新的方法,，可以找到相互結(jié)合的一組蛋白。這些蛋白構(gòu)成可以用顯微鏡觀測到的“分子機(jī)器”,，并在腦部搜尋神經(jīng)細(xì)胞的“發(fā)動機(jī)房”——被稱為“突觸”的神經(jīng)細(xì)胞間連接,。
為了找到這組被稱為MASCs（MAGUK Associated Signaling Complexes）的關(guān)鍵蛋白，研究人員引進(jìn)了一種之前應(yīng)用于酵母細(xì)胞的研究方法,。該方法利用一個“分子鉤”附著于小鼠腦細(xì)胞內(nèi)一種蛋白質(zhì)上,。然后，研究人員抓住分子鉤,，將其拉出,，發(fā)現(xiàn)它帶出另外100多種蛋白。這些蛋白中包含數(shù)十種引起腦部疾病的蛋白,。這100多種蛋白不僅包含許多疾病蛋白,，還包含控制神經(jīng)細(xì)胞間傳遞信息、控制學(xué)習(xí)與記憶的蛋白,。
Grant教授稱,，這項研究是基礎(chǔ)科學(xué)和臨床科學(xué)的重要結(jié)合。這一發(fā)現(xiàn)表明,，分子機(jī)器本身是許多重要腦部疾病的根源,。這也是一個全新的研究項目，通過探求學(xué)習(xí)和記憶的基本機(jī)制,，將有助于了解大腦內(nèi)部是如何運(yùn)作,。(生物谷Bioon.com)
生物谷推薦原始出處：
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.
