Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA.
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
Cell Rep. 2022 Mar 22;38(12):110556. doi: 10.1016/j.celrep.2022.110556.
Many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), lead to the selective degeneration of discrete cell types in the CNS despite the ubiquitous expression of many genes linked to disease. Therapeutic advancement depends on understanding the unique cellular adaptations that underlie pathology of vulnerable cells in the context of disease-causing mutations. Here, we employ bacTRAP molecular profiling to elucidate cell type-specific molecular responses of cortical upper motor neurons in a preclinical ALS model. Using two bacTRAP mouse lines that label distinct vulnerable or resilient projection neuron populations in motor cortex, we show that the regulation of oxidative phosphorylation (Oxphos) pathways is a common response in both cell types. However, differences in the baseline expression of genes involved in Stem and the handling of reactive oxygen species likely lead to the selective degeneration of the vulnerable cells. These results provide a framework to identify cell-type-specific processes in neurodegenerative disease.
许多神经退行性疾病，如肌萎缩侧索硬化症（ALS），尽管与疾病相关的许多基因普遍表达，但导致中枢神经系统中离散细胞类型的选择性退化。治疗进展取决于了解在致病突变背景下易损细胞病理学基础上的独特细胞适应。在这里，我们采用 bacTRAP 分子分析阐明了临床前 ALS 模型中皮质上运动神经元的细胞类型特异性分子反应。使用两种 bacTRAP 小鼠系，标记运动皮层中不同的易损或有弹性的投射神经元群体，我们表明氧化磷酸化（Oxphos）途径的调节是两种细胞类型的共同反应。然而，参与 Stem 和活性氧处理的基因的基线表达差异可能导致易损细胞的选择性退化。这些结果为识别神经退行性疾病中的细胞类型特异性过程提供了框架。
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