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首页> 外文期刊>Molecular brain >Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes
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Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes

机译：人体死后突触蛋白质组完整性筛选，用于突触后复合体的蛋白质组学研究

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Background Synapses are fundamental components of brain circuits and are disrupted in over 100 neurological and psychiatric diseases. The synapse proteome is physically organized into multiprotein complexes and polygenic mutations converge on postsynaptic complexes in schizophrenia, autism and intellectual disability. Directly characterising human synapses and their multiprotein complexes from post-mortem tissue is essential to understanding disease mechanisms. However, multiprotein complexes have not been directly isolated from human synapses and the feasibility of their isolation from post-mortem tissue is unknown. Results Here we establish a screening assay and criteria to identify post-mortem brain samples containing well-preserved synapse proteomes, revealing that neocortex samples are best preserved. We also develop a rapid method for the isolation of synapse proteomes from human brain, allowing large numbers of post-mortem samples to be processed in a short time frame. We perform the first purification and proteomic mass spectrometry analysis of MAGUK Associated Signalling Complexes (MASC) from neurosurgical and post-mortem tissue and find genetic evidence for their involvement in over seventy human brain diseases. Conclusions We have demonstrated that synaptic proteome integrity can be rapidly assessed from human post-mortem brain samples prior to its analysis with sophisticated proteomic methods. We have also shown that proteomics of synapse multiprotein complexes from well preserved post-mortem tissue is possible, obtaining structures highly similar to those isolated from biopsy tissue. Finally we have shown that MASC from human synapses are involved with over seventy brain disorders. These findings should have wide application in understanding the synaptic basis of psychiatric and other mental disorders.
机译：背景技术突触是大脑回路的基本组成部分，在100多种神经和精神疾病中被破坏。突触蛋白质组在物理上被组织成多蛋白复合物，并且在精神分裂症，自闭症和智力障碍中，多基因突变收敛于突触后复合物。从死后组织中直接表征人类突触及其多蛋白复合物对于理解疾病机制至关重要。然而，尚未从人突触中直接分离出多蛋白复合物，并且从验尸组织中分离它们的可行性尚不清楚。结果在这里，我们建立了筛选测定法和标准，以鉴定含有保存完好的突触蛋白质组的验尸大脑样本，揭示出新皮层样本保存得最好。我们还开发了一种从人脑中分离突触蛋白质组的快速方法，可以在短时间内处理大量验尸样品。我们从神经外科和验尸组织中进行了MAGUK相关信号复合物（MASC）的首次纯化和蛋白质组质谱分析，并发现了涉及其超过70种人类脑部疾病的遗传证据。结论我们已经证明，在使用复杂的蛋白质组学方法进行分析之前，可以从人类验尸的大脑样本中快速评估突触蛋白质组的完整性。我们还显示，从保存完好的尸检组织中突触多蛋白复合物的蛋白质组学是可能的，获得与从活检组织分离的结构高度相似的结构。最后，我们已经表明，来自人类突触的MASC与70多种脑部疾病有关。这些发现应广泛用于理解精神病和其他精神疾病的突触基础。

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