Vicario Nunzio, Castrogiovanni Paola, Imbesi Rosa, Giallongo Sebastiano, Mannino Giuliana, Furno Debora Lo, Giuffrida Rosario, Zappalà Agata, Li Volti Giovanni, Tibullo Daniele, Di Rosa Michelino, Parenti Rosalba
Department of Biomedical and Biotechnological Sciences, Section of Physiology, School of Medicine, University of Catania, 95125 Catania, Italy.
Department of Biomedical and Biotechnological Sciences, Section of Anatomy, Histology and Movement Sciences, School of Medicine, University of Catania, 95125 Catania, Italy.
Biomedicines. 2022 Sep 10;10(9):2246. doi: 10.3390/biomedicines10092246.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motoneurons (MNs) with a fatal outcome. The typical degeneration of cortico-spinal, spinal, and bulbar MNs, observed in post-mortem biopsies, is associated with the activation of neuroimmune cells. GJA1, a member of the connexins (Cxs) gene family, encodes for connexin 43 (Cx43), a core gap junctions (GJs)- and hemichannels (HCs)-forming protein, involved in cell death, proliferation, and differentiation. Recently, Cx43 expression was found to play a role in ALS pathogenesis. Here, we used microarray and RNA-seq datasets from the NCBI of the spinal cord of control (NDC) and ALS patients, which were stratified according to the GJA1 gene expression. Genes that positively or negatively correlated to GJA1 expression were used to perform a genomic deconvolution analysis (GDA) using neuroimmune signatures. Expression analysis revealed a significantly higher GJA1 expression in the MNs of ALS patients as compared to NDC. Gene deconvolution analysis revealed that positively correlated genes were associated with microglia activation, whereas negatively correlated genes were associated with neuronal activation profiles. Moreover, gene ontology analysis, performed on genes characterizing either microglia or neuronal signature, indicated immune activation or neurogenesis as main biological processes. Finally, using a synthetic analysis of drugs able to revert the GJA1 transcriptomic signatures, we found a specific drug profile for ALS patients with high GJA1 expression levels, composed of amlodipine, sertraline, and prednisolone. In conclusion, our exploratory study suggests GJA1 as a new neuro-immunological gene correlated to microglial cellular profile in the spinal cord of ALS patients. Further studies are warranted to confirm these results and to evaluate the therapeutic potential of drugs able to revert typical GJA1/CX43 signature in ALS patients.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，影响运动神经元（MNs），最终导致死亡。在死后活检中观察到的皮质脊髓、脊髓和延髓运动神经元的典型退化与神经免疫细胞的激活有关。GJA1是连接蛋白（Cxs）基因家族的成员，编码连接蛋白43（Cx43），这是一种形成核心间隙连接（GJs）和半通道（HCs）的蛋白质，参与细胞死亡、增殖和分化。最近，发现Cx43表达在ALS发病机制中起作用。在这里，我们使用了来自美国国立医学图书馆（NCBI）的对照（NDC）和ALS患者脊髓的微阵列和RNA测序数据集，这些数据集根据GJA1基因表达进行了分层。与GJA1表达呈正相关或负相关的基因用于使用神经免疫特征进行基因组反卷积分析（GDA）。表达分析显示，与NDC相比，ALS患者的运动神经元中GJA1表达显著更高。基因反卷积分析显示，正相关基因与小胶质细胞激活有关，而负相关基因与神经元激活谱有关。此外，对表征小胶质细胞或神经元特征的基因进行的基因本体分析表明，免疫激活或神经发生是主要的生物学过程。最后，通过对能够逆转GJA1转录组特征的药物进行综合分析，我们发现了一种针对GJA1表达水平高的ALS患者的特定药物组合，由氨氯地平、舍曲林和泼尼松龙组成。总之，我们的探索性研究表明GJA1是一个与ALS患者脊髓中小胶质细胞特征相关的新的神经免疫基因。需要进一步的研究来证实这些结果，并评估能够逆转ALS患者典型GJA1/CX43特征的药物的治疗潜力。
