美国加州大学旧金山分校的David H. Rowitch和Arnold R. Kriegstein等研究人员合作，揭示了多发性硬化症（MS）的神经脆弱性和细胞谱系多样性。2019年9月5日出版的《自然》发表了这项成果。

研究人员使用单核RNA测序来评估MS病变中多个细胞谱系中的表达变化，并使用多重原位杂交验证了结果。研究人员发现在脑膜炎症的上皮质层中存在选择性易损特质并且出现表达CUX2基因的兴奋性投射神经元的丢失；这种MS神经元类群表现出应激途径基因和长非编码RNA的上调。应激的少突胶质细胞、反应性星形胶质细胞和活化的小胶质细胞的特征强烈地反应在MS斑块的边缘。值得注意的是，单核RNA测序通过其摄取和核周导入髓鞘质的转录本鉴定出吞噬小胶质细胞和/或巨噬细胞，并通过功能性小鼠和人类细胞培养实验得到证实。这些研究结果表明谱系和区域特异性转录组学变化与选择性皮质神经元损伤和胶质细胞激活有关，从而促进MS病变的进展。

据了解， MS是一种神经炎症性疾病，在早期阶段具有复发缓解型病程，这种疾病在皮质灰质与皮质下白质中具有不同的病变特征并且存在慢性阶段的神经变性。

附：英文原文

Title: Neuronal vulnerability and multilineage diversity in multiple sclerosis

Author: Lucas Schirmer, Dmitry Velmeshev, Staffan Holmqvist, Max Kaufmann, Sebastian Werneburg, Diane Jung, Stephanie Vistnes, John H. Stockley, Adam Young, Maike Steindel, Brian Tung, Nitasha Goyal, Aparna Bhaduri, Simone Mayer, Jan Broder Engler, Omer A. Bayraktar, Robin J. M. Franklin, Maximilian Haeussler, Richard Reynolds, Dorothy P. Schafer, Manuel A. Friese, Lawrence R. Shiow, Arnold R. Kriegstein, David H. Rowitch

Issue&Volume: Volume 573 Issue 7772

Abstract: Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsingremitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.

DOI: 10.1038/s41586-019-1404-z

Source:https://www.nature.com/articles/s41586-019-1404-z