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Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration.
Human Molecular Genetics ( IF 3.5 ) Pub Date : 2020-04-13 , DOI: 10.1093/hmg/ddaa069 Danyllo Oliveira 1 , David A Morales-Vicente 2, 3 , Murilo S Amaral 2 , Livia Luz 4 , Andrea L Sertié 5 , Felipe S Leite 1 , Claudia Navarro 6 , Carolini Kaid 1 , Joyce Esposito 1 , Ernesto Goulart 1 , Luiz Caires 1 , Luciana M Alves 1 , Uirá S Melo 1 , Thalita Figueiredo 1, 7 , Miguel Mitne-Neto 8 , Oswaldo K Okamoto 1 , Sergio Verjovski-Almeida 2, 3 , Mayana Zatz 1
Human Molecular Genetics ( IF 3.5 ) Pub Date : 2020-04-13 , DOI: 10.1093/hmg/ddaa069 Danyllo Oliveira 1 , David A Morales-Vicente 2, 3 , Murilo S Amaral 2 , Livia Luz 4 , Andrea L Sertié 5 , Felipe S Leite 1 , Claudia Navarro 6 , Carolini Kaid 1 , Joyce Esposito 1 , Ernesto Goulart 1 , Luiz Caires 1 , Luciana M Alves 1 , Uirá S Melo 1 , Thalita Figueiredo 1, 7 , Miguel Mitne-Neto 8 , Oswaldo K Okamoto 1 , Sergio Verjovski-Almeida 2, 3 , Mayana Zatz 1
Affiliation
Amyotrophic lateral sclerosis type 8 (ALS8) is an autosomal dominant form of ALS, which is caused by pathogenic variants in the VAPB gene. Here we investigated five ALS8 patients, classified as ‘severe’ and ‘mild’ from a gigantic Brazilian kindred, carrying the same VAPB mutation but displaying different clinical courses. Copy number variation and whole exome sequencing analyses in such individuals ruled out previously described genetic modifiers of pathogenicity. After deriving induced pluripotent stem cells (iPSCs) for each patient (N = 5) and controls (N = 3), motor neurons were differentiated, and high-throughput RNA-Seq gene expression measurements were performed. Functional cell death and oxidative metabolism assays were also carried out in patients’ iPSC-derived motor neurons. The degree of cell death and mitochondrial oxidative metabolism were similar in iPSC-derived motor neurons from mild patients and controls and were distinct from those of severe patients. Similar findings were obtained when RNA-Seq from such cells was performed. Overall, 43 genes were upregulated and 66 downregulated in the two mild ALS8 patients when compared with severe ALS8 individuals and controls. Interestingly, significantly enriched pathways found among differentially expressed genes, such as protein translation and protein targeting to the endoplasmic reticulum (ER), are known to be associated with neurodegenerative processes. Taken together, the mitigating mechanisms here presented appear to maintain motor neuron survival by keeping translational activity and protein targeting to the ER in such cells. As ALS8 physiopathology has been associated with proteostasis mechanisms in ER–mitochondria contact sites, such differentially expressed genes appear to relate to the bypass of VAPB deficiency.
中文翻译:
来自具有不同临床病程的 ALS8 患者的 iPSC 衍生运动神经元中的不同基因表达谱表明减轻神经变性的途径。
8 型肌萎缩侧索硬化 (ALS8) 是 ALS 的常染色体显性遗传形式,由VAPB基因中的致病性变异引起。在这里,我们调查了 5 名 ALS8 患者,这些患者来自一个巨大的巴西亲属,被归类为“严重”和“轻度”,携带相同的VAPB突变,但表现出不同的临床病程。这些个体的拷贝数变异和全外显子组测序分析排除了先前描述的致病性遗传修饰物。在为每位患者 ( N = 5) 和对照 ( N = 3),运动神经元被分化,并进行了高通量 RNA-Seq 基因表达测量。还在患者的 iPSC 衍生的运动神经元中进行了功能性细胞死亡和氧化代谢测定。轻症患者和对照组的 iPSC 衍生运动神经元的细胞死亡和线粒体氧化代谢程度相似,与重症患者不同。当从这些细胞中进行 RNA-Seq 时,也获得了类似的发现。总体而言,与严重 ALS8 个体和对照相比,两名轻度 ALS8 患者中有 43 个基因上调,66 个基因下调。有趣的是,在差异表达的基因中发现了显着丰富的通路,例如蛋白质翻译和蛋白质靶向内质网(ER),已知与神经退行性过程有关。总之,这里提出的缓解机制似乎通过在这些细胞中保持翻译活动和蛋白质靶向内质网来维持运动神经元的存活。由于 ALS8 病理生理学与 ER-线粒体接触位点的蛋白质稳态机制有关,因此这种差异表达的基因似乎与绕过 VAPB 缺陷有关。
更新日期:2020-04-13
中文翻译:
来自具有不同临床病程的 ALS8 患者的 iPSC 衍生运动神经元中的不同基因表达谱表明减轻神经变性的途径。
8 型肌萎缩侧索硬化 (ALS8) 是 ALS 的常染色体显性遗传形式,由VAPB基因中的致病性变异引起。在这里,我们调查了 5 名 ALS8 患者,这些患者来自一个巨大的巴西亲属,被归类为“严重”和“轻度”,携带相同的VAPB突变,但表现出不同的临床病程。这些个体的拷贝数变异和全外显子组测序分析排除了先前描述的致病性遗传修饰物。在为每位患者 ( N = 5) 和对照 ( N = 3),运动神经元被分化,并进行了高通量 RNA-Seq 基因表达测量。还在患者的 iPSC 衍生的运动神经元中进行了功能性细胞死亡和氧化代谢测定。轻症患者和对照组的 iPSC 衍生运动神经元的细胞死亡和线粒体氧化代谢程度相似,与重症患者不同。当从这些细胞中进行 RNA-Seq 时,也获得了类似的发现。总体而言,与严重 ALS8 个体和对照相比,两名轻度 ALS8 患者中有 43 个基因上调,66 个基因下调。有趣的是,在差异表达的基因中发现了显着丰富的通路,例如蛋白质翻译和蛋白质靶向内质网(ER),已知与神经退行性过程有关。总之,这里提出的缓解机制似乎通过在这些细胞中保持翻译活动和蛋白质靶向内质网来维持运动神经元的存活。由于 ALS8 病理生理学与 ER-线粒体接触位点的蛋白质稳态机制有关,因此这种差异表达的基因似乎与绕过 VAPB 缺陷有关。