Liu Xiaoyun, Miller Benjamin R, Rebec George V, Clemmer David E
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, USA.
J Proteome Res. 2007 Aug;6(8):3134-42. doi: 10.1021/pr070092s. Epub 2007 Jul 11.
Liquid chromatography (LC) coupled with mass spectrometry (MS) and database assignment methods have been used to conduct a large-scale proteome survey of the R6/2 mouse model of Huntington's disease (HD). Although the neuropathological mechanisms of HD are not known, the mutant huntingtin gene that causes the disease is thought to alter gene transcription, leading to a cascade of neurotoxic events. In this report, we have focused on characterizing changes in the brain proteome associated with HD pathophysiology. Differences in the relative abundances of proteins (R6/2 compared to wild type) in brain tissue from the striatum and cortex, two primary loci of dysfunction in HD, were assessed by using a label-free approach based on calibrations to internal standards. In total, assignments were made for approximately 400 proteins. A set of criteria was used to establish 160 high confidence assignments, approximately 30% of which appear to show differences in expression relative to wild type (WT) animals. Many of the proteins that were differentially expressed are known to be associated with neurotransmission and likely play key roles in HD etiology. This study is the first to report that the majority of differentially expressed proteins in the striatum are up-regulated, while the majority of the expressed proteins in the cortex are down-regulated. The differentially expressed proteins identified in this proteomic screen may be potential biomarkers and drug targets for HD and may further our understanding of the disease pathology.
液相色谱（LC）与质谱（MS）联用以及数据库匹配方法已被用于对亨廷顿舞蹈病（HD）的R6/2小鼠模型进行大规模蛋白质组学研究。尽管HD的神经病理学机制尚不清楚，但人们认为导致该疾病的突变亨廷顿基因会改变基因转录，进而引发一系列神经毒性事件。在本报告中，我们着重于表征与HD病理生理学相关的脑蛋白质组变化。通过基于内标校准的无标记方法，评估了来自纹状体和皮质（HD中两个主要功能障碍位点）的脑组织中蛋白质相对丰度的差异（R6/2与野生型相比）。总共鉴定了约400种蛋白质。使用一组标准确定了160个高可信度的鉴定结果，其中约30%相对于野生型（WT）动物似乎表现出表达差异。许多差异表达的蛋白质已知与神经传递有关，并且可能在HD病因学中起关键作用。本研究首次报道，纹状体中大多数差异表达的蛋白质上调，而皮质中大多数差异表达的蛋白质下调。在该蛋白质组学筛选中鉴定出的差异表达蛋白质可能是HD的潜在生物标志物和药物靶点，并可能加深我们对该疾病病理的理解。
