Neuronal vulnerability and multilineage diversity in multiple sclerosis
Neuronal vulnerability and multilineage diversity in multiple sclerosis
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DOI：
10.1038/s41586-019-1404-z
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发表时间：
2019-09-05
期刊：
影响因子：
64.8
通讯作者：
Rowitch, David H.
中科院分区：
文献类型：
--
作者：
Schirmer, Lucas;Velmeshev, Dmitry;Rowitch, David H.
多发性硬化症（MS）是一种神经炎症性疾病，在早期阶段具有复发-缓解的病程，在皮质灰质与皮质下白色物质中具有不同的病变特征，并且在慢性阶段具有神经变性。在这里，我们使用单核RNA测序来评估MS病变中多个细胞系的表达变化，并使用多重原位杂交验证结果。我们发现选择性脆弱性和兴奋性CUX 2表达投射神经元的损失在上层皮层脑膜炎症的基础;这样的MS神经元群体表现出应激途径基因和长的非编码RNA的上调。应激少突胶质细胞、反应性星形胶质细胞和活化的小胶质细胞的特征最强烈地映射到MS斑块的边缘。值得注意的是，单核RNA测序鉴定了吞噬小胶质细胞和/或巨噬细胞的摄取和髓磷脂转录核周输入，证实了功能性小鼠和人类培养试验。我们的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活化相关，有助于MS病变的进展。
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting 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.