Swindell William R
Division of Hospital Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9175, USA.
NeuroSci. 2025 Jul 16;6(3):65. doi: 10.3390/neurosci6030065.
Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron failure and poor prognosis. This study performed a meta-analysis of gene expression datasets that compared bulk-processed post-mortem spinal cord from ALS and control (CTL) patients. The analysis included 569 samples (454 ALS, 115 CTL) from 348 individuals (262 ALS, 86 CTL). Patterns of differential expression bias, related to mRNA abundance, gene length and GC content, were discernable from individual studies but attenuated by meta-analysis. A total of 213 differentially expressed genes (DEGs) were identified (144 ALS-increased, 69 ALS-decreased). ALS-increased DEGs were most highly expressed by microglia and associated with MHC class II, immune response and leukocyte activation. ALS-decreased DEGs were abundantly expressed by mature oligodendrocytes (e.g., the MOL5 phenotype) and associated with myelin production, plasma membrane and sterol metabolism. Comparison to spatial transcriptomics data showed that DEGs were prominently expressed in white matter, with increased DEG expression strongest in the ventral/lateral white matter. These results highlight white matter as the spinal cord region most strongly associated with the shifts in mRNA abundance observed in bulk-processed tissues. These shifts can be explained by attrition of mature oligodendrocytes and an ALS-emergent microglia phenotype that is partly shared among neurodegenerative conditions.
肌萎缩侧索硬化症（ALS）的特征是上下运动神经元功能衰竭且预后不良。本研究对基因表达数据集进行了荟萃分析，该数据集比较了ALS患者和对照（CTL）患者死后脊髓的批量处理样本。分析包括来自348名个体（262名ALS患者，86名CTL患者）的569个样本（454个ALS样本，115个CTL样本）。与mRNA丰度、基因长度和GC含量相关的差异表达偏差模式在个体研究中是可辨别的，但在荟萃分析中减弱。总共鉴定出213个差异表达基因（DEG）（144个在ALS中增加，69个在ALS中减少）。在ALS中增加的DEG在小胶质细胞中表达最高，并与MHC II类、免疫反应和白细胞活化相关。在ALS中减少的DEG在成熟少突胶质细胞（如MOL5表型）中大量表达，并与髓鞘生成、质膜和甾醇代谢相关。与空间转录组学数据的比较表明，DEG在白质中显著表达，在腹侧/外侧白质中DEG表达增加最为强烈。这些结果突出了白质是与批量处理组织中观察到的mRNA丰度变化最密切相关的脊髓区域。这些变化可以用成熟少突胶质细胞的损耗和一种在神经退行性疾病中部分共享的ALS出现的小胶质细胞表型来解释。
