Kentucky IDeA Networks of Biomedical Research Excellence Bioinformatics Core, Department of Neuroscience Training, University of Louisville, Louisville, KY 40292, USA.
Brown Cancer Center Bioinformatics Core, Center for Integrative Environmental Health Sciences Biostatistics and Informatics Facility Core, Department of Medicine, University of Louisville, Louisville, KY 40292, USA.
Int J Mol Sci. 2024 Nov 7;25(22):11957. doi: 10.3390/ijms252211957.
Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease affecting approximately 3 million people globally. Despite rigorous research on MS, aspects of its development and progression remain unclear. We utilized a publicly available RNA-seq dataset (GSE138614) consisting of the post-mortem white matter tissues of five donors without any neurological disorders and ten MS patient donors. We investigated gene expression levels correlated with tissue inflammation and alternative splicing to identify possible pathological isoforms in MS tissues. We identified RNA-binding motifs, differentially expressed RNA-binding proteins, and single-nucleotide polymorphisms (SNPs) to unravel possible mechanisms of alternative splicing. Genes with expression changes that were positively correlated with tissue inflammation were enriched in the immune system and receptor interaction pathways. Genes showing a negative correlation were enriched in nervous system development and in metabolic pathways. A comparison of normal-appearing white matter (NAWM) and active or chronic active lesions within the same donors identified genes playing roles in immunity, white matter injury repair, and remyelination. We identified exon skipping events and spontaneous SNPs in membrane-associated ring-CH-type finger-1 (), UDP glycosyltransferase-8 (), and other genes important in autoimmunity and neurodegeneration. Overall, we identified unique genes, pathways, and novel splicing events that can be further investigated as potential novel drug targets for MS treatment.
多发性硬化症（MS）是一种影响全球约 300 万人的自身免疫性神经退行性疾病。尽管对 MS 进行了严格的研究，但它的发展和进展的某些方面仍不清楚。我们利用了一个公开的 RNA-seq 数据集（GSE138614），其中包含五个没有任何神经障碍的供体的死后白质组织和十个 MS 患者供体。我们研究了与组织炎症和可变剪接相关的基因表达水平，以鉴定 MS 组织中可能存在的病理性同工型。我们确定了 RNA 结合基序、差异表达的 RNA 结合蛋白和单核苷酸多态性（SNP），以揭示可变剪接的可能机制。与组织炎症呈正相关的表达变化的基因在免疫系统和受体相互作用途径中富集。表现出负相关的基因在神经系统发育和代谢途径中富集。对同一供体的正常外观白质（NAWM）和活跃或慢性活跃病变进行比较，鉴定出在免疫、白质损伤修复和髓鞘再生中起作用的基因。我们鉴定了外显子跳跃事件和膜相关环-CH 型手指-1（）、UDP 糖基转移酶-8（）和其他在自身免疫和神经退行性变中重要的基因中的自发 SNP。总的来说，我们鉴定了独特的基因、途径和新的剪接事件，这些事件可以进一步研究作为 MS 治疗的潜在新药物靶点。
