Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion
Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion
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DOI：
10.3233/jad-181123
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Ferrer, Isidro
中科院分区：
文献类型：
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作者：
Andres-Benito, Pol;Gelpi, Ellen;Ferrer, Isidro
背景：伴有TDP-43免疫反应包涵体的额颞叶变性(FTLD-TDP)可能表现为散发性(sFTLD-TDP)，或与多种基因的突变有关，包括C9ORF72非编码区的扩展(C9FTLD)。目的：分析C9FRF72非编码区在额叶皮质的差异RNA和蛋白表达，并与先前观察到的额叶皮质TDP-TDP和TDP-43包涵体肌萎缩侧索硬化症进行比较。结果：芯片杂交区分了C9FTLD中与DNA重组、RNA剪接调控、RNA聚合酶转录、髓鞘合成、钙调节和泛素-蛋白酶体系统相关的基因转录异常；在相同的组织样本中进行蛋白质组学分析，发现c9FTLD的异常蛋白质表达涉及细胞凋亡、炎症、氨基酸代谢、碳水化合物代谢、膜脂代谢、微管动力学、线粒体形态、神经发生、神经传递、吞噬、受体介导的内吞作用、活性氧物种的合成以及钙信号转导。结论：转录组和蛋白质组学以及衍生数据的生物信息学处理揭示了c9FTLD额叶皮质类似的改变途径，但这些方法鉴定出不同的RNA和蛋白质。如果在评估人类死后大脑样本时谨慎对待观察结果，那么组合的非靶向组学是破译FTLD中改变的分子途径的一种有价值的方法。
Background: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD).Objective: Analysis of differentialmRNAand protein expression in the frontal cortex in c9FLTDand evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions.Methods: Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls.Results: Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD.Conclusion: Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted '-omics' is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples.