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Longitudinal transcriptomic analysis of altered pathways in a CHMP2Bintron5-based model of ALS-FTD.
Neurobiology of Disease ( IF 5.1 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.nbd.2019.104710 Robin Waegaert 1 , Sylvie Dirrig-Grosch 1 , Florian Parisot 1 , Céline Keime 2 , Alexandre Henriques 1 , Jean-Philippe Loeffler 1 , Frédérique René 1
Neurobiology of Disease ( IF 5.1 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.nbd.2019.104710 Robin Waegaert 1 , Sylvie Dirrig-Grosch 1 , Florian Parisot 1 , Céline Keime 2 , Alexandre Henriques 1 , Jean-Philippe Loeffler 1 , Frédérique René 1
Affiliation
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Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with currently no cure. These two diseases share a clinical continuum with overlapping genetic causes. Mutations in the CHMP2B gene are found in patients with ALS, FTD and ALS-FTD. To highlight deregulated mechanisms occurring in ALS-FTD linked to the CHMP2B gene, we performed a whole transcriptomic study on lumbar spinal cord from CHMP2Bintron5 mice, a model that develops progressive motor alterations associated with dementia symptoms reminiscent of both ALS and FTD. To gain insight into the transcriptomic changes taking place during disease progression this study was performed at three stages: asymptomatic, symptomatic and end stage. We showed that before appearance of motor symptoms, the major disrupted mechanisms were linked with the immune system/inflammatory response and lipid metabolism. These processes were progressively replaced by alterations of neuronal electric activity as motor symptoms appeared, alterations that could lead to motor neuron dysfunction. To investigate overlapping alterations in gene expression between two ALS-causing genes, we then compared the transcriptome of symptomatic CHMP2Bintron5 mice with the one of symptomatic SOD1G86R mice and found the same families deregulated providing further insights into common underlying dysfunction of biological pathways, disrupted or disturbed in ALS. Altogether, this study provides a database to explore potential new candidate genes involved in the CHMP2Bintron5-based pathogenesis of ALS, and provides molecular clues to further understand the functional consequences that diseased neurons expressing CHMP2B mutant may have on their neighbor cells.
中文翻译：
在基于CHMP2Bintron5的ALS-FTD模型中改变路径的纵向转录组学分析。
肌萎缩性侧索硬化症和额颞痴呆是目前无法治愈的两种神经退行性疾病。这两种疾病具有重叠遗传原因的临床连续性。在患有ALS，FTD和ALS-FTD的患者中发现了CHMP2B基因的突变。为了突出在与CHMP2B基因相关的ALS-FTD中发生的失控机制，我们对CHMP2Bintron5小鼠的腰脊髓进行了完整的转录组学研究，该模型发展出与痴呆症状相关的进行性运动改变，让人联想到ALS和FTD。为了深入了解疾病进展过程中发生的转录组变化，本研究分三个阶段进行：无症状，有症状和终末期。我们发现在出现运动症状之前，主要的破坏机制与免疫系统/炎症反应和脂质代谢有关。随着运动症状的出现，这些过程逐渐被神经元电活动的改变所取代，这些改变可能导致运动神经元功能障碍。为了研究两个引起ALS的基因之间基因表达的重叠变化，我们将有症状的CHMP2Bintron5小鼠的转录组与有症状的SOD1G86R小鼠中的一个进行了比较，发现相同的家族被解除管制，从而为常见的潜在生物学途径功能障碍（被破坏或干扰）提供了进一步的见解。在ALS中。总之，这项研究提供了一个数据库，用于探索与CHMP2Bintron5的ALS发病机制有关的潜在新候选基因，
更新日期：2019-12-17
中文翻译：
在基于CHMP2Bintron5的ALS-FTD模型中改变路径的纵向转录组学分析。
肌萎缩性侧索硬化症和额颞痴呆是目前无法治愈的两种神经退行性疾病。这两种疾病具有重叠遗传原因的临床连续性。在患有ALS，FTD和ALS-FTD的患者中发现了CHMP2B基因的突变。为了突出在与CHMP2B基因相关的ALS-FTD中发生的失控机制，我们对CHMP2Bintron5小鼠的腰脊髓进行了完整的转录组学研究，该模型发展出与痴呆症状相关的进行性运动改变，让人联想到ALS和FTD。为了深入了解疾病进展过程中发生的转录组变化，本研究分三个阶段进行：无症状，有症状和终末期。我们发现在出现运动症状之前，主要的破坏机制与免疫系统/炎症反应和脂质代谢有关。随着运动症状的出现，这些过程逐渐被神经元电活动的改变所取代，这些改变可能导致运动神经元功能障碍。为了研究两个引起ALS的基因之间基因表达的重叠变化，我们将有症状的CHMP2Bintron5小鼠的转录组与有症状的SOD1G86R小鼠中的一个进行了比较，发现相同的家族被解除管制，从而为常见的潜在生物学途径功能障碍（被破坏或干扰）提供了进一步的见解。在ALS中。总之，这项研究提供了一个数据库，用于探索与CHMP2Bintron5的ALS发病机制有关的潜在新候选基因，
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