Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis.
Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis.
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DOI：
10.1016/j.nbd.2020.104877
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发表时间：
2020-07
影响因子：
6.1
通讯作者：
Chandler SH
中科院分区：
文献类型：
--
作者：
Liu W;Venugopal S;Majid S;Ahn IS;Diamante G;Hong J;Yang X;Chandler SH
肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，在这种疾病中，遍及大脑和脊髓的运动神经元逐渐退化，导致肌肉萎缩、瘫痪和死亡。最近使用ALS动物模型的研究表明，脊髓运动系统的ALS发病机制涉及多种细胞类型（如星形胶质细胞和小胶质细胞）。为了确定ALS在脑干中的细胞脆弱性和协调口腔运动功能的细胞类型特异性机制，我们使用高通量Drop-seq方法进行了平行单细胞RNA测序（scRNA-seq）分析。我们在出生后100天分别从SOD1野生型和突变型症状小鼠脑干中分离1894和3199个细胞。我们恢复了主要已知的细胞类型和神经元亚群，如中间神经元和运动神经元，三叉神经节（TG）外周感觉神经元，以及以前未表征的中间神经元亚型。我们发现大多数细胞类型在ALS小鼠中表现出转录组改变。单个细胞群的差异表达基因（DEGs）揭示了许多途径中细胞类型的特异性改变，包括先前已知的ALS途径，如炎症（小胶质细胞）、应激反应（室管膜和未表征的细胞群）、神经发生（星形胶质细胞、少突胶质细胞、神经元）、突触组织和传递（小胶质细胞、少突胶质细胞前体细胞和神经元亚型）和线粒体功能（未表征的细胞群）。在SOD1突变脑干中改变的其他细胞类型特异性过程包括运动神经元（轴突再生、兴奋性基础的电压门控钠钾通道、钾离子运输）、三叉感觉神经元（参与感觉知觉的温度刺激检测）和对有毒物质的细胞反应（未表征的细胞群）。发现了不同细胞类型（如Malat1）以及特定细胞类型的基因变异。重要的是，来自不同细胞类型的deg与文献中已知的ALS基因重叠，并与现有人类ALS全基因组关联研究（GWAS）中的顶点重叠，这暗示了ALS基因在ALS发病机制中发挥作用的潜在细胞类型。我们在单细胞分辨率上的分子研究为广泛使用的ALS小鼠模型中脑干细胞类型、基因和通路的改变提供了全面的见解。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons throughout the brain and spinal cord progressively degenerate resulting in muscle atrophy, paralysis and death. Recent studies using animal models of ALS implicate multiple cell-types (e.g., astrocytes and microglia) in ALS pathogenesis in the spinal motor systems. To ascertain cellular vulnerability and cell-type specific mechanisms of ALS in the brainstem that orchestrates oral-motor functions, we conducted parallel single cell RNA sequencing (scRNA-seq) analysis using the high-throughput Drop-seq method. We isolated 1894 and 3199 cells from the brainstem of wildtype and mutant SOD1 symptomatic mice respectively, at postnatal day 100. We recovered major known cell types and neuronal subpopulations, such as interneurons and motor neurons, and trigeminal ganglion (TG) peripheral sensory neurons, as well as, previously uncharacterized interneuron subtypes. We found that the majority of the cell types displayed transcriptomic alterations in ALS mice. Differentially expressed genes (DEGs) of individual cell populations revealed cell-type specific alterations in numerous pathways, including previously known ALS pathways such as inflammation (in microglia), stress response (ependymal and an uncharacterized cell population), neurogenesis (astrocytes, oligodendrocytes, neurons), synapse organization and transmission (microglia, oligodendrocyte precursor cells, and neuronal subtypes), and mitochondrial function (uncharacterized cell populations). Other cell-type specific processes altered in SOD1 mutant brainstem include those from motor neurons (axon regeneration, voltage-gated sodium and potassium channels underlying excitability, potassium ion transport), trigeminal sensory neurons (detection of temperature stimulus involved in sensory perception), and cellular response to toxic substances (uncharacterized cell populations). DEGs consistently altered across cell types (e.g., Malat1), as well as cell-type specific DEGs, were identified. Importantly, DEGs from various cell types overlapped with known ALS genes from the literature and with top hits from an existing human ALS genome-wide association study (GWAS), implicating the potential cell types in which the ALS genes function with ALS pathogenesis. Our molecular investigation at single cell resolution provides comprehensive insights into the cell types, genes and pathways altered in the brainstem in a widely used ALS mouse model.
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影响因子：
4.4
作者：
Pedotti P;'t Hoen PA;Vreugdenhil E;Schenk GJ;Vossen RH;Ariyurek Y;de Hollander M;Kuiper R;van Ommen GJ;den Dunnen JT;Boer JM;de Menezes RX
通讯作者：
de Menezes RX
影响因子：
5.3
作者：
Heath PR;Kirby J;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
14.5
作者：
Hedlund, Eva;Karlsson, Martin;Isacson, Ole
通讯作者：
Isacson, Ole
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
影响因子：
16.6
作者：
Arneson D;Zhang G;Ying Z;Zhuang Y;Byun HR;Ahn IS;Gomez-Pinilla F;Yang X
通讯作者：
Yang X