The microglial reaction is a hallmark of neurodegenerative conditions, and elements thereof may exert differential effects on disease progression, either worsening or ameliorating severity. In amyotrophic lateral sclerosis (ALS), a syndrome characterized by cytoplasmic aggregation of TDP-43 protein and atrophy of motor neurons in the cortex and spinal cord, the transcriptomic signatures of microglia during disease progression are incompletely understood. Here, we performed longitudinal RNAseq analysis of cortical and spinal cord microglia from rNLS8 mice, in which doxycycline-regulatable expression of human TDP-43 (hTDP-43) in the cytoplasm of neurons recapitulates many features of ALS. Transgene suppression in rNLS8 mice leads to functional, anatomical and electrophysiological resolution that is dependent on a microglial reaction that is concurrent with recovery rather than disease onset. We identified basal differences between the gene expression profiles of microglia dependent on localization in spinal cord or cortex. Microglia subjected to chronic hTDP-43 overexpression demonstrated transcriptomic changes in both locations. We noted strong upregulation of Apoe, Axl, Cd63, Clec7a, Csf1, Cst7, Igf1, Itgax, Lgals3, Lilrb4, Lpl and Spp1 during late disease and recovery. Importantly, we identified a distinct suite of differentially expressed genes associated with each phase of disease progression and recovery. Differentially expressed genes were associated with chemotaxis, phagocytosis, inflammation, and production of neuroprotective factors. These data provide new insights into the microglial reaction in TDP-43 proteinopathy. Genes differentially expressed during progression and recovery may provide insight into a unique instance in which the microglial reaction promotes functional recovery after neuronal insult.

中文翻译：

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TDP-43 蛋白病 rNLS8 小鼠模型中的小胶质细胞转录组分析揭示了与神经退行性进展和恢复相关的离散表达谱

小胶质细胞反应是神经退行性疾病的标志，其元素可能对疾病进展产生不同的影响，无论是恶化还是改善严重程度。在肌萎缩侧索硬化症 (ALS) 中，一种以 TDP-43 蛋白的细胞质聚集和皮质和脊髓运动神经元萎缩为特征的综合征，在疾病进展过程中小胶质细胞的转录组学特征尚不完全清楚。在这里，我们对 rNLS8 小鼠的皮质和脊髓小胶质细胞进行了纵向 RNAseq 分析，其中多西环素可调节人 TDP-43 (hTDP-43) 在神经元细胞质中的表达概括了 ALS 的许多特征。rNLS8 小鼠中的转基因抑制导致功能性，解剖学和电生理学分辨率取决于与恢复同时发生的小胶质细胞反应，而不是疾病发作。我们确定了依赖于脊髓或皮层定位的小胶质细胞基因表达谱之间的基础差异。遭受慢性 hTDP-43 过表达的小胶质细胞在两个位置都表现出转录组的变化。我们注意到 Apoe、Axl、Cd63、Clec7a、Csf1、Cst7、Igf1、Itgax、Lgals3、Lilrb4、Lpl 和 Spp1 在疾病晚期和恢复期间的强烈上调。重要的是，我们确定了与疾病进展和恢复的每个阶段相关的一组独特的差异表达基因。差异表达的基因与趋化性、吞噬作用、炎症和神经保护因子的产生有关。这些数据为 TDP-43 蛋白病中的小胶质细胞反应提供了新的见解。在进展和恢复过程中差异表达的基因可以提供对小胶质细胞反应促进神经元损伤后功能恢复的独特实例的洞察。