Novel proteomic changes in brain mitochondria provide insights into mitochondrial dysfunction in mouse models of Huntington's disease
Novel proteomic changes in brain mitochondria provide insights into mitochondrial dysfunction in mouse models of Huntington's disease
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DOI：
10.1016/j.mito.2019.03.004
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发表时间：
2019-07-01
期刊：
影响因子：
4.4
通讯作者：
Fox, Jonathan H.
中科院分区：
文献类型：
--
作者：
Agrawal, Sonal;Fox, Jonathan H.
亨廷顿氏病（HD）是一种进行性的最终致命的疾病，由亨廷顿蛋白（HTT）基因中编码谷氨酰胺的CAG扩增引起，其导致主要在纹状体和纹状体-皮质脑区域的变性。线粒体功能障碍是HD发病机制的一个重要方面。在这里，我们使用了人类HD的R6/2和YAC 128 HD小鼠模型，它们表达不同的HTT转基因并且具有不同的进展率，来识别HD脑线粒体蛋白质组特征。通过二维SDS-PAGE电泳和MALDI-TOF/TOF质谱法比较HD和野生型同窝小鼠的大脑皮质线粒体制备物。蛋白质组学分析推断17和12个差异表达的蛋白质，分别在12周R6/2和15个月YAC 128 HD小鼠，与对照组相比。Peroxiredoxin 3、stress-70、DJ-1、异柠檬酸脱氢酶[NAD] α亚基和ATP合酶亚基D在两种模型中差异表达。利用PANTHER（Protein Analysis Through Evolutionary Relationships）分类系统，我们发现推测的蛋白质参与氧化应激防御、氧化磷酸化、柠檬酸循环、丙酮酸代谢、细胞凋亡、蛋白质折叠和铁代谢。尽管HIT转基因、年龄、遗传背景和疾病阶段存在差异，但常见的线粒体蛋白质组变化在中度（YAC 128）和晚期（R6/2）HD小鼠模型中是显著的。这些发现确定了小鼠模型中HD线粒体的蛋白质组特征，其中包括以前未识别的蛋白质。
Huntington's disease (HD) is a progressive ultimately fatal disorder caused by a glutamine-encoding CAG expansion in the huntingtin (HTT) gene that results in degeneration mainly in striatal and cerebro-cortical brain regions. Mitochondrial dysfunction is one important facet of HD pathogenesis. Here we used R6/2 and YAC128 HD mouse models of human HD, that express different HTT transgenes and have different progression rates, to identify HD brain mitochondrial proteomic signatures. Cerebral cortical mitochondrial preparations from HD and wild-type litter mate mice were compared by two-dimensional SDS-PAGE electrophoresis and MALDI-TOF/TOF mass spectrometry. Proteomic analyses inferred 17 and 12 differentially expressed proteins, respectively in 12 week R6/2 and 15 month YAC128 HD mice, compared to controls. Peroxiredoxin 3, stress-70, DJ-1, isocitrate dehydrogenase [NAD] alpha subunit and ATP synthase subunit D were differentially expressed in both models. Using the PANTHER (Protein ANalysis THrough Evolutionary Relationships) classification system we show that the inferred proteins are involved in oxidative stress defense, oxidative phosphorylation, the citric acid cycle, pyruvate metabolism, apoptosis, protein folding and iron metabolism. Common mitochondrial proteomic changes are significant in mouse models of middle (YAC128) and advanced (R6/2) HD despite differences in the HIT transgenes, age, genetic background and disease stage. The findings identify a proteomic signature of HD mitochondria in mouse models that includes previously unrecognized proteins.